CN103124592B - Compositions and methods for preparing nanoformulations and systems for nano-delivery using focused acoustics - Google Patents

Compositions and methods for preparing nanoformulations and systems for nano-delivery using focused acoustics Download PDF

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CN103124592B
CN103124592B CN201180041736.8A CN201180041736A CN103124592B CN 103124592 B CN103124592 B CN 103124592B CN 201180041736 A CN201180041736 A CN 201180041736A CN 103124592 B CN103124592 B CN 103124592B
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mixture
particle size
formulation
particles
method according
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CN103124592A (en
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卡尔·贝克特
小詹姆斯·A·劳格哈恩
斯里坎斯·卡库马努
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科瓦里斯股份有限公司
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    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01FMIXING, e.g. DISSOLVING, EMULSIFYING, DISPERSING
    • B01F11/00Mixers with shaking, oscillating, or vibrating mechanisms
    • B01F11/02Mixing by means of high-frequency, e.g. ultrasonic vibrations, e.g. jets impinging against a vibrating plate
    • B01F11/0283Mixing by means of high-frequency, e.g. ultrasonic vibrations, e.g. jets impinging against a vibrating plate transmitting the vibratory energy by means of a fluid, e.g. by means of air shock waves
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2/00Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
    • B01J2/18Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic using a vibrating apparatus
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01FMIXING, e.g. DISSOLVING, EMULSIFYING, DISPERSING
    • B01F2215/00Auxiliary or complementary information in relation with mixing
    • B01F2215/04Technical information in relation with mixing
    • B01F2215/0413Numerical information
    • B01F2215/0418Geometrical information
    • B01F2215/0431Numerical size values, e.g. diameter of a hole or conduit, area, volume, length, width, or ratios thereof
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01FMIXING, e.g. DISSOLVING, EMULSIFYING, DISPERSING
    • B01F2215/00Auxiliary or complementary information in relation with mixing
    • B01F2215/04Technical information in relation with mixing
    • B01F2215/0413Numerical information
    • B01F2215/0436Operational information
    • B01F2215/0454Numerical frequency values
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01FMIXING, e.g. DISSOLVING, EMULSIFYING, DISPERSING
    • B01F2215/00Auxiliary or complementary information in relation with mixing
    • B01F2215/04Technical information in relation with mixing
    • B01F2215/0413Numerical information
    • B01F2215/0436Operational information
    • B01F2215/0477Numerical time values
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01FMIXING, e.g. DISSOLVING, EMULSIFYING, DISPERSING
    • B01F3/00Mixing, e.g. dispersing, emulsifying, according to the phases to be mixed
    • B01F3/08Mixing, e.g. dispersing, emulsifying, according to the phases to be mixed liquids with liquids; Emulsifying
    • B01F3/0807Emulsifying
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781Aspects relating to microreactors
    • B01J2219/00925Irradiation
    • B01J2219/00932Sonic or ultrasonic vibrations

Abstract

聚焦超声声处理(focused ultrasonic acoustic processing)用于制备范围为约10nm至约50微米(例如,1微米至20微米)或约10nm至约400nm(例如,10nm至100nm)的制剂颗粒。 Focused ultrasound sonication (focused ultrasonic acoustic processing) for the preparation of the formulation particles range from about 10nm to about 50 microns (e.g., 1 to 20 microns), or from about 10nm to about 400 nm (e.g., 10nm to 100nm) is. 制剂(例如,纳米制剂)可包括混悬剂(例如,纳米混悬剂)、乳剂(例如,纳米乳剂)或其他小颗粒系统。 Formulation (e.g., nano-formulation) may include suspending agents (e.g., nano suspensions), emulsions (e.g., nanoemulsions) systems, or other small particles. 制剂可用作治疗剂的递送系统。 The delivery system formulation useful therapeutic agents. 制剂还可包括微米或亚微米大小的颗粒分散在溶剂中的混悬剂。 Formulations may also include suspensions of micron or submicron sized particles are dispersed in a solvent. 或者,制剂可包括生物活性剂和包封所述生物活性剂的载体化合物如表面活性剂(例如,含有药物、多核苷酸等的脂质体/微团)。 Alternatively, the formulation may include a carrier compound and the bioactive agent encapsulating the biologically active agent such as surfactants (e.g., liposomes containing a drug, such as a polynucleotide / micelles). 在一些情况下,制剂中颗粒大小分布的多分散指数小于0.1。 In some cases, the polydispersity index of the particle size distribution in the formulation is less than 0.1. 制剂可合适地使用导致混合物平均颗粒大小降低的聚焦声能来制备。 Suitable formulations may be prepared using lead focused acoustic energy to reduce the average particle size of the mixture. 或者,合适的制剂可使用聚焦声以不降低所述混合物平均颗粒大小的方式来制备。 Alternatively, a suitable focused acoustic formulations may be prepared so as not to reduce the average particle size of the mixture was manner.

Description

使用聚焦声制备用于纳米递送之纳米制剂和系统的组合物和方法 Compositions and methods for the preparation of focused acoustic nanoformulations and delivery system of the nano

[0001] 本申请要求2011年1月21日提交的美国临时申请no. 61/434, 941和2010年7 月1日提交的美国临时申请no. 61/360, 700的权益,其通过引用整体并入本文。 [0001] This application claims priority to US provisional application no 2011 Nian 1, filed May 21 in. 61/434, US provisional application no 61/360, rights and interests. 941 and 700 of July 1, 2010 filed by reference in its entirety incorporated herein.

背景技术 Background technique

[0002] 1.发明领域 [0002] 1. Field of the Invention

[0003] 本文中描述的一些方面涉及使用聚焦声能(focused acoustic energy)来制备用于纳米递送的制剂(例如,纳米制剂(nanoformulation))和/或系统。 [0003] Some aspects described herein relates to the preparation of the formulation (e.g., nanoformulations (nanoformulation)) and / or delivery systems for nano using focused acoustic energy (focused acoustic energy). 在一些情况下,本文中讨论的纳米递送系统可用于与递送生物活性剂相关的领域。 In some cases, nano-delivery system discussed herein may be used in the fields associated with the delivery of bioactive agents.

[0004] 2.相关领域 [0004] 2. Related art

[0005] 声处理系统(acoustic treatment system)可用于使样品暴露于声场(acoustic field)。 [0005] The sound processing system (acoustic treatment system) can be used to expose the sample to a sound field (acoustic field). 可进行声处理的样品包括遗传物质(例如,DNA、RNA)、组织材料(例如,骨、结缔组织、血管组织)、植物材料(例如,叶、种子)、细胞以及其他物质。 Sonicated sample may include genetic material (e.g., DNA, RNA), tissue material (e.g., bone, connective tissue, vascular tissue), plant materials (e.g., leaves, seeds), cells and other substances. 声处理系统可用于处理生物和域非生物物品。 Sonication system for processing items of biological and non-biological field. 在一些安排下,声能(acoustic energy)可相对强烈,引起样品材料被破碎、裂解或以其他方式破坏。 In some arrangements, the acoustic energy (acoustic energy) may be relatively strong, causing sample material to be crushed, lysed or otherwise damaged. 例如,可将含有多个细胞的样品暴露于声处理,以致细胞膜和其他组分被破坏或以其他方式降解,从而使DNA或其他遗传物质释放到液体中。 For example, a sample containing a plurality of cells exposed to sonication, the cell membrane and other components that are damaged or otherwise degraded, so that the DNA or other genetic material is released into the liquid. 然后可收集所述遗传物质并将其用于多种类型的分析。 The genetic material can then be collected and used for various types of analyzes. 声处理系统使用声换能器(acoustic transducer)来为这些过程产生合适的声场。 Sonication system using an acoustic transducer (acoustic transducer) for generating a sound field suitable for these processes. 所述声场被聚焦或以其他方式安排,从而引起对样品材料的期望作用。 The sound field is focused or otherwise arranged to cause a desired effect on the sample material. 此类系统的实例在美国专利No. 6, 948, 843 ;6, 719, 449 ; 7, 521,023 ;和7, 687, 026 中描述。 Examples of such system is U.S. Patent No. 6, 948, 843 in; 6, 719, 449; 7, 521,023; and 7, 687, 026 is described.

[0006] 发明概述 [0006] Summary of the Invention

[0007] 本文中描述的一些方面涉及使用聚焦超声声处理(focused ultrasonic acoustic processing)的制备纳米制剂的组合物和方法。 [0007] Some aspects described herein relate to compositions and methods for preparing nanoformulations focused ultrasound sonication (focused ultrasonic acoustic processing) of. 在纳米制剂的制备中,可将聚焦超声声能(focused ultrasonic acoustic energy)施用于含有至少两种不同组合物的混合物,以形成非常小之颗粒的紧密分布(tigh distribution)(例如,具有低多分散指数(polydispersity index))。 Preparation of Nano formulation, ultrasound may be focused acoustic energy (focused ultrasonic acoustic energy) comprising a mixture of at least two different compositions applied to, to form a very tight distribution of small particles (tigh distribution) (e.g., having a low multiple The dispersion index (polydispersity index)). 在一些情况下,这样的小颗粒具有微米或纳米(亚微米)大小的特征。 In some cases, such small particles having a micron or nanometer features (submicron) size. 本文中所讨论的纳米制剂可包含在混悬剂(例如,纳米混悬剂)、乳剂(例如,纳米乳剂)或包含小颗粒之其他系统中的微颗粒和/或纳米颗粒。 Nano formulations discussed herein may be included in a suspension (e.g., nano suspensions), emulsions (e.g., nanoemulsions), or other systems comprising microparticles of small particles and / or nanoparticles. 在一些实施方案中,尽管不是必需的,纳米制剂也还用作生物活性剂(例如药物和/或其他治疗性化合物)的纳米大小的递送系统。 In some embodiments, although not required, the formulation can also be used as nano-biologically active agent (e.g. a drug and / or other therapeutic compounds) nano-sized delivery systems. 例如,纳米制剂可包含例如药物(pharmaceutical)、营养品(nutraceutical) 和/或药用化妆品(cosmeceutical)的化合物。 For example, a compound such as a drug can be nanoformulations (Pharmaceutical), nutritional supplements (Nutraceutical) and / or cosmeceutical (cosmeceutical) comprises. 纳米制剂可包含分散在溶剂中的微米或亚微米大小之颗粒的混悬剂。 Formulation may comprise nano-dispersed in a solvent suspension of micron or submicron sized particles of. 或者,纳米制剂可包含生物活性剂和载体化合物(例如包封(encapsulate)生物活性剂(例如包含在脂质体中的药物)的表面活性剂)。 Alternatively, the formulation may comprise nano-biologically active agent and a carrier compound (e.g. encapsulation (Encapsulate) bioactive agent (e.g. a drug contained in the liposomes) a surfactant).

[0008] 在纳米制剂的制备中,含有两种不同的组合物的混合物可放置于容器中,并暴露于小于2厘米大小的声能聚焦区(focal zone)。 [0008] Preparation of Nano formulation, containing a mixture of two different compositions may be placed in a container, and exposed to the acoustic energy of less than 2 cm in size focal zone (focal zone). 聚焦的声场可由声能来源(acoustic energy source)产生,所述来源在合适的功率水平下运作一定的时间,从而在所述混合物充分暴露于声场聚焦区之后可产生含有平均大小为约IOnm至约50微米且相对紧密分布之多个颗粒的纳米制剂。 Focused by the acoustic energy source (acoustic energy source) the sound field is generated, the source operation a certain time at a suitable power level to fully expose the mixture after the sound field focal zone may be generated with an average size of about IOnm to about 50 microns and nano-formulations of relatively closely spaced plurality of particles. 在一些情况下,在所述混合物经受聚焦声处理之前混合物中的平均颗粒大小大于100微米,或大于200微米。 In some cases, the mixture is subjected to an average particle size of the mixture prior to focused acoustic treatment is greater than 100 microns, or greater than 200 microns. 根据所述混合物的处理方式,所产生的平均颗粒大小可小于10微米、小于1微米、在IOOnm至1微米之间或在IOnm至IOOnm之间。 The treatment of the mixture, the average particle size of less than 10 microns can be produced, less than 1 micron, between 1 micron or IOOnm between IOnm to IOOnm. 在一些实施方案中,所产生的平均颗粒大小的范围是IOnm至400nm。 In some embodiments, the average particle size range produced is IOnm to 400nm.

[0009] 在一些实施方案中,可用聚焦声能来处理具有多种组合物和起始平均颗粒大小分布的混合物,处理方式为降低所述混合物的平均颗粒大小和/或以其他方式产生单峰的并具有低多分散指数的颗粒大小分布。 [0009] In some embodiments, the focused acoustic energy can be used to deal with the mixture, and the treatment of various compositions starting mean particle size distribution of the average particle size of the mixture and / or reduce the generation of singlet otherwise and having a low polydispersity index of the particle size distribution. 虽然,在混合物中降低颗粒大小和/或制备某种颗粒大小分布在一些情况下是有利的,但这不是本公开内容所必需的方面。 Although, particle size reduction and / or preparation of certain particle size distribution in some cases be advantageous in the mixture, but this is not essential aspect of the disclosure. 在一些实施方案中, 可根据聚焦声法对具有多种组合物的混合物进行合适的处理,从而使所述混合物的平均颗粒大小不降低,而是组装(assemble)或以其他方式形成期望大小范围的颗粒。 In some embodiments, the method may be performed in accordance with focused acoustic mixtures having various compositions suitable processing, so that the average particle size of the mixture did not decrease, but the assembly (Assemble) formed in a desired size range, or otherwise particle.

[0010] 在一个举例说明性的实施方案中,提供了制备纳米制剂的方法。 [0010] In one illustrative embodiment, a method of preparing nano formulation. 所述方法包括在容器中提供混合物,所述混合物包含第一组合物和第二组合物;使具有约100千赫至约100 兆赫之频率和具有小于约2厘米大小之聚焦区的聚焦声能传送穿过所述容器的壁,从而使所述混合物至少部分地置于所述聚焦区中;和至少部分地通过将所述混合物暴露于所述聚焦区一段时间以在混合物中形成多个颗粒,在所述混合物暴露于所述聚焦区所述一段时间后,所述多个颗粒具有约IOnm至约50微米的平均大小。 The method comprises providing a mixture in a vessel, said mixture comprising a first composition and the second composition; to make about 100 kHz to about 100 MHz and the frequency of focused acoustic having about 2 cm less than the size of the focal zone can be transmitting through the wall of the container, so that the mixture is at least partially disposed in the focal zone; and a mixture of at least part of said period of time by exposure to said focal region to form a plurality of particles in the mixture after exposure of the mixture to the focal zone for the period of time, said plurality of particles having an average size of about IOnm to about 50 microns.

[0011] 在另一个举例说明性的实施方案中,提供了用于制备纳米制剂的系统。 [0011] In another illustrative embodiment, a system for preparing nano formulation. 所述系统包括容器;包含第一组合物和第二组合物的混合物,所述混合物置于所述容器中;和声能来源,其与所述容器隔开且在其外部并且适于发射聚焦声能,所述聚焦声能具有约IOOkHz 至约IOOMHz的频率和穿过所述容器壁的具有小于约2cm大小的聚焦区,从而使所述混合物至少部分地置于聚焦区中,其中,在所述混合物暴露于聚焦区一段时间之后,所述混合物包含平均大小为约IOnm至约50微米的多个颗粒。 The system includes a container; a mixture comprising a first composition and a second composition, the mixture is placed in the container; acoustic energy source, which is separated from the container and the outside thereof and adapted to transmit focusing acoustic energy, the acoustic energy focused to about IOOkHz size of less than about 2cm frequency and through the focal region of the container wall about IOOMHz so that the mixture is at least partially disposed in the focal zone, wherein after the mixture is exposed to a period of the focal zone, said mixture containing an average size of about IOnm to a plurality of particles of about 50 microns.

[0012] 本发明的多个实施方案提供了某些优点。 [0012] Embodiments of the present invention provide certain advantages. 本发明的所有实施方案并不共有同样的优点,并且共有同样优点的那些实施方案并不是在所有情况下都共有所述同样的优点。 All embodiments of the present invention is not shared the same advantages and the same advantages of those embodiments consensus not all share the same advantages in all cases.

[0013] 下文中参照附图详细地描述了本发明的其他特征和优点以及本发明多个实施方案的结构。 [0013] Hereinafter describes the structure and other features and advantages of the present invention, a plurality of embodiments of the present invention in detail with reference to the drawings.

[0014] 附图简述 [0014] BRIEF DESCRIPTION

[0015] 参照附图通过举例的方式来描述本发明的一些非限制性实施方案,所述附图是示意性的且并不旨在按比例绘制。 [0015] will be described with reference to the accompanying drawings of some non-limiting embodiments of the present invention by way of example, the drawings are schematic and are not intended to be drawn to scale. 在图中,图示的每个相同或几乎相同的组件通常由同一数字表示。 In the drawings, each identical or nearly identical component illustrated is typically represented by the same numbers. 为了清楚的目的,并不是在每幅图中对每个组件都进行标记,当图示对于本领域普通技术人员理解本发明来说并不必需时,也并不示出本发明每个实施方案的每个组件。 For purposes of clarity, not every component may be labeled for in each figure, when the present invention is shown not necessarily to be understood to those of ordinary skill in the art, it is not shown in each embodiment of the present invention of each component. 图中: Figure:

[0016] 图1示出了根据一个举例说明性实施方案之声处理系统的示意图; [0016] FIG. 1 shows a schematic view of an illustrative embodiment of the sound processing system according to one embodiment example;

[0017] 图2图示了根据一个举例说明性实施方案之另一声处理系统的示意图; [0017] FIG 2 illustrates a schematic diagram of another illustrative embodiment of the sound processing system according to one example of embodiment;

[0018] 图3描述了根据一个举例说明性实施方案之另一声处理系统的示意图; [0018] Figure 3 depicts a schematic diagram of another illustrative embodiment of the sound processing system according to one example of embodiment;

[0019] 图4示出了根据一个举例说明性实施方案之不同声处理系统的示意图; [0019] FIG. 4 shows a schematic view of different acoustic processing system according to an illustrative embodiment of an example embodiment;

[0020] 图5图示了根据一个举例说明性实施方案之另一声处理系统的示意图; [0020] FIG 5 illustrates a schematic diagram of another illustrative embodiment of the sound processing system according to one example of embodiment;

[0021] 图6示出了根据实施例的声处理之前和之后混合物中颗粒的显微照片; [0021] FIG. 6 shows a photomicrograph of the particles and then the mixture before processing in accordance with an embodiment of the sound;

[0022] 图7描述了根据一个实施例在处理混合物期间随时间之平均颗粒大小的图; [0022] FIG. 7 depicts a mean particle size of the time, according to one embodiment during the treatment with the mixture;

[0023] 图8图示了根据另一个实施例在处理混合物期间随时间之平均颗粒大小的图; [0023] FIG. 8 illustrates a further embodiment of FIG time with average particle size of the mixture during processing;

[0024] 图9描述了根据一个实施例在处理混合物期间随时间之平均颗粒大小的图; [0024] FIG 9 depicts the average particle size of the time, according to one embodiment during the treatment with the mixture;

[0025] 图10图示了根据一个实施例在处理混合物期间随时间之平均颗粒大小的图; [0025] FIG. 10 illustrates one embodiment of the FIG time with average particle size of the mixture during processing;

[0026] 图11示出了根据另一个实施例的混合物颗粒大小分布的图; [0026] FIG. FIG. 11 shows a mixture of particles according to another embodiment of the size distribution;

[0027] 图12示出了根据不同实施例的混合物颗粒大小分布的图; [0027] FIG. FIG. 12 shows the particle size distribution of the mixture according to various embodiments;

[0028] 图13图示了处理前根据一个实施例的混合物颗粒大小分布的图; [0028] FIG. 13 illustrates the particle size distribution of a mixture of a pretreatment according to the embodiment;

[0029] 图14图示了聚焦声处理之后根据图13的实施例的混合物颗粒大小分布的图; After [0029] FIG. 14 illustrates a focused acoustic processing of FIG particle size distribution of the mixture according to the embodiment of Figure 13;

[0030] 图15图示了聚焦声处理之后根据图13的实施例的混合物颗粒大小分布的另一幅图; [0030] FIG. 15 illustrates another one after the process of FIG focused acoustic mixture of particles size distribution according to the embodiment of Figure 13;

[0031] 图16描述了根据一个实施例的混合物颗粒大小分布的图;和 [0031] FIG. 16 depicts a mixture of the particle size distribution according to an embodiment; and

[0032] 图17描述了根据另一个实施例的混合物颗粒大小分布的图。 [0032] FIG. 17 depicts a view of another embodiment of a mixture of particulate size distribution.

[0033] 发明详述 [0033] DETAILED DESCRIPTION

[0034] 本公开内容涉及用于制备具有窄分布之期望颗粒大小分布的纳米制剂的利用聚焦声的系统和方法,并且所述系统和方法还可重复、可控、快速产生结果、避免样品材料的交叉污染,并且是等温的(即,避免样品的过热)。 [0034] The present disclosure relates to a system and method for preparing a focused acoustic nanoformulations desired narrow distribution of particle size distribution, and the system and method may also be repeated, controlled, rapid generation of results, avoiding the sample material cross-contamination, and isothermal (i.e., to avoid overheating of the sample). 这样的纳米制剂和以简单、方便的方式产生它们的能力可用于增进治疗性递送的现有方法,以及用于治疗性递送的制备系统。 Such nano-formulation and in a simple, convenient way to produce conventional method may be used to enhance their ability to deliver a therapeutic, and for the preparation of a therapeutic delivery system. 合适的纳米制剂可包括混悬剂、乳剂或不同的小颗粒系统中的颗粒。 Suitable formulations may include a nano-particle suspensions, emulsions or small particles of different systems. 在一些情况下,纳米制剂可用于递送治疗剂。 In some cases, nanoformulations be used to deliver therapeutic agents. 本文提供的纳米制剂的实例包括分散在溶剂中微米或亚微米大小之颗粒的混悬剂,或配置在载体组合物(例如,载体中的脂质体)中的生物活性剂。 Examples of nano-formulations provided herein include microns dispersed in a solvent or a suspension of particles of submicron size, arranged in the carrier composition or the biologically active agent (e.g., liposome carrier) was added. 如本文所述, 纳米制剂可被认为是包含亚微米大小之颗粒的制剂。 As described herein, it may be regarded as nano-formulation comprising a formulation of a submicron particle size.

[0035] 根据所描述的方法生产的纳米制剂可包含平均颗粒大小为约IOnm至约50微米(或在一些情况下为约IOnm至约400nm)的混合物。 [0035] The methods described nanoformulation produced an average particle size of about IOnm to about 50 microns (or in some cases from about IOnm to about 400nm) may comprise a mixture. 在一些实施方案中,颗粒大小分布相对紧密,例如具有小于〇. 1的多分散指数。 In some embodiments, the particle size distribution is relatively compact, for example less than square. 1 polydispersity index. 在一些实施方案中,纳米制剂可通过使具有多种组合物的混合物经受聚焦声能来制备,制备方式为降低混合物的平均颗粒大小和/或以其他方式(例如,通过形成脂质体)处理混合物,以产生具有低多分散指数的单峰颗粒大小分布。 In some embodiments, the nano-formulation may be prepared by reacting the mixture was subjected to a variety of focused acoustic composition, prepared in a manner to reduce the average particle size and / or a mixture otherwise (e.g., by the formation of liposomes) Processing mixture to produce a low polydispersity index having a unimodal particle size distribution. 在另一些实施方案中,纳米制剂可通过向混合物施用聚焦声能来制备,制备方式不显著降低所述混合物的平均颗粒大小,而是通过将组分组装在一起(例如形成脂质体)而形成期望大小范围的颗粒。 In other embodiments, the nano-formulations can be prepared by focused acoustic administered to the mixture prepared as not to significantly reduce the average particle size of the mixture, but by the components assembled together (e.g., formation of liposomes) and forming a desired particle size range.

[0036] 本发明人已经认识并领会到,用市场上现有的几种药物,通过制药工业生产的大量化学组合物是亲脂性(可溶性差)化合物。 [0036] The present inventors have recognized and appreciated that, with several drugs available on the market, a large number of chemical composition by the pharmaceutical industry is the production of a lipophilic (poorly soluble) compound. 作为如此差溶解度的结果,药剂趋于表现出生物半衰期短、生物利用度差、明显的不良作用和整体降低的稳定性。 As a result of such poor solubility, the agents tend to exhibit short biological half-life, poor bioavailability, stability and overall significant reduction in adverse effects. 然后是在临床前阶段评价此类组合物,所述组合物经常作为水基混悬剂而经口服用。 Such compositions are then evaluated in a preclinical stage, the composition is often used as a water-based suspensions and oral administration. 与服用溶液制剂相比,服用水基混悬剂不利的一面是可能出现不利的体内结果,例如降低的生物利用度和更高的对象间可变性。 Compared with the solution formulation administered, taking water-based suspensions downside it is disadvantageous in vivo results possible, for example, between the reduced bioavailability and greater variability of the object. 相反地,使用常规方法但却不用无毒水平的赋形剂和/或不消耗相当大的资源就不易获得溶液制剂,从而使多个化合物的早期评价无法实现。 In contrast, conventional methods using excipients and / or early evaluation does not consume considerable resources is not easy to obtain a solution formulation, so that a plurality but not a non-toxic level of the compound can not be achieved.

[0037] 生产具有期望(并且相对小)颗粒大小的混悬剂可有助于缓和前述问题。 [0037] produce a desired (and relatively small) particle size may help to alleviate the aforementioned problems suspensions. 本发明人认识并领会到,快速且方便地形成跨越一系列样品容量和浓度、无污染(例如,来自重复使用可重复使用的探针)或降解(例如,由于过度加热)的具有期望颗粒大小之混悬剂的常规方法并不理想。 The present inventors have recognized and appreciated that, quickly and conveniently formed across a range of sample volumes and concentrations, pollution (e.g., from a reuse reusable probes) or degradation (e.g., due to excessive heating) having a desired particle size conventional methods of suspension is not ideal. 传统方法通常产生宽的颗粒大小分布(例如,高多分散指数),这与紧密、窄的颗粒大小分布(例如,低多分散指数)相反。 Conventional methods typically produce a broad particle size distribution (e.g., high polydispersity index), which is close, narrow particle size distribution (e.g., low polydispersity index) opposite. 配制用于临床前经口服用之简单混悬剂的常规方法包括声波处理、匀浆(homogenization)、微流化、搅拌和/或使用用于提升同质性的赋形剂(例如具有表面活性的湿润剂或聚合物)。 Formulated in conventional methods by simple suspension of preclinical orally include sonication, homogenization (homogenization), microfluidization, stirring and / or excipients for lifting homogeneity (e.g. with surfactant wetting agents or polymers).

[0038] 尚未发现机械匀浆理想地用于生产混悬剂,因为所述技术在制剂中产生泡沫,并且不提供用于减轻交叉污染的方法。 [0038] Not found over mechanically homogenized suspensions for the production, because the foam formulation techniques, and does not provide a method for reducing cross-contamination. 此外,微流化除了允许在处理室中的交叉污染之外,还有产生非常大量热的趋势。 Further, microfluidization addition to allowing cross-contamination in the processing chamber, there are a very large amount of heat trend. 微流化的其他缺点包括处理后样品必须用热交换器冷却,和样品必须频繁地多次通过微流化系统,致使样品材料不可完全回收。 Other disadvantages include microfluidization after treatment sample must be cooled with a heat exchanger, and samples to multiple passes through the microfluidic system, so that the sample material is frequently not fully recovered. 作为额外的步骤,配制前研磨化合物为整个处理添加了更多的时间,且由于需求而进行更多的步骤,所以引入了更大的产率损失。 As an additional step to prepare compound is added prior to grinding more time for the whole process, and since the demand for more step, so that the introduction of a greater yield loss.

[0039] 虽然超声已用于多种诊断、治疗和研究目的,但是生物物理学、化学和机械的作用通常仅被经验性地理解。 [0039] While ultrasound has been used in a variety of diagnostic, therapeutic and research purposes, but the role of biophysical, chemical and mechanical are generally understood only empirically. 在材料处理中对声能(sonic energy或acoustic energy)的一些使用包括"超声处理",其是机械破坏的未精制处理,涉及将发射低千赫(kHz)范围(例如, 15kHz)能量的未聚焦超声来源直接浸入被处理材料的流体混悬剂中。 In the process some of the material used for the acoustic energy (sonic energy or acoustic energy) include "sonication", which is a mechanical disruption treatment of unrefined, relates to emit low kilohertz (kHz) range (e.g., 15kHz) is not energy focused ultrasound source is directly immersed in a fluid suspension of material to be treated. 因此,声能由于声波的未聚焦和随机性而产生不一致的结果,并且易于诱导样品过热,这是因为能量被分散、吸收和/或未与靶标适当地对齐。 Thus, acoustic energy generated due to the random and unfocused acoustic wave inconsistent results, and easy to induce overheating the sample, because the energy is dispersed, absorbed and / or properly aligned with a target.

[0040] 与先前使用声能相反,本文中所描述的在纳米制剂的制备中使用"聚焦声"有显著的益处,包括以下列出的那些。 [0040] In contrast with prior use sonic energy, as described herein using the "focused acoustic" There are significant benefits in the manufacture of nano-formulations, including those listed below. 聚焦声提供独特的益处,其允许产生具有期望颗粒大小分布的纳米制剂(例如,具有窄单峰分布的合适的颗粒大小范围)。 Focused acoustic provide unique benefits, which allows the production of nano-formulation having a desired particle size distribution (e.g., having a suitable particle size range narrow monomodal distribution). 在声处理期间,聚焦声还为纳米制剂的处理和产生提供极少的(或没有)样品加热(即,提供等温处理)。 During sonication, focused sound is also provided to process and produce little nanoformulations (or not) the sample is heated (i.e., to provide an isothermal process). 组合物可在包容环境(contained environment)(即,封闭系统)下处理,使得无污染风险的无菌非接触式操作成为可能。 The composition may be processed in a contained environment (contained environment) (i.e., a closed system) at such a sterile non-contact operation becomes possible pollution risk. 与制备纳米制剂的常规方法(例如,研磨、微流化、匀浆等)相比, 最终回收产率显著提高(例如,100%的材料回收)。 Compared with the conventional method of preparing nano-formulation (e.g., milling, microfluidization, homogenization, etc.), the final recovery yield was significantly improved (e.g., 100% recycled material). 聚焦声处理在小量(例如,小于IOmL) 和大量(例如,大于250mL)处理体积之间可高度地扩展。 Focused acoustic processing small (e.g., less than IOmL) and the volume between large (e.g., greater than 250 mL) highly scalable process. 聚焦声可用于制备具有宽范围浓度的纳米制剂,其中对于不同的混合物(在混合物中具有大幅不同浓度的特定组合物)出现基本相同的处理结果(例如,在具有浓度低至lmg/mL和高至100mg/mL的不同混合物的聚焦声处理之后,结果可以是相似的)。 Focused acoustic useful for making a wide range of concentrations nanoformulation, wherein substantially the same processing result occurs for different mixtures (having a particular composition significantly different concentrations in the mixture) (e.g., up to lmg / mL and having a high concentration after to 100mg / mL of a mixture of different focused acoustic processing result may be similar). 本文中描述的聚焦声法还可涉及简单的处理操作, 与常规超声处理或制备纳米制剂的方法相比,需要更少的操作人力和更低的操作技能组合(skill set)。 Focused acoustic method described herein may also involve a simple processing operation, compared with the conventional ultrasound method of treating or nano preparation prepared, it requires less manpower and operation of lower operating skill (skill set). 本文中讨论的使用聚焦声法的纳米制剂可表现出延长的保质期,极少或没有活性成分(例如,治疗剂)的降解,而这可发生于形成纳米制剂的常规方法中。 As used herein, the focused acoustic methods discussed nanoformulations may exhibit extended shelf-life, little or no active ingredient (e.g., therapeutic agent) degradation, which can occur in a conventional method of forming a nano formulation. 聚焦声使得能够在混合物中使用宽范围的表面活性剂和分散介质;以及能够使用含低浓度表面活性剂和分散介质的混合物,或可能完全不使用表面活性剂和分散介质。 Such that the focused acoustic surfactant and a dispersion medium can be used in a wide range of mixture; and mixtures may be used containing a low concentration of surfactant and the dispersion medium, or may be completely without the use of a surfactant and a dispersion medium. 此外,聚焦声能可用于裂解细胞,并因此杀死细菌和病毒,因此提供将目标组合物灭菌的方法。 Furthermore, focused acoustic energy may be used to lyse the cells, and therefore kill bacteria and viruses, thus providing a method for sterilizing a target composition. 可根据C 〇VariS,InC, Woburn, MA提供的适应性聚焦声(adaptive focused acoustics, AFA)法来使用聚焦声。 May be used in accordance with focused acoustic adaptive focused acoustic C 〇VariS, InC, Woburn, MA provided (adaptive focused acoustics, AFA) method.

[0041] 本文中呈现的系统和方法将聚焦声用于可控、快速且方便地制备具有紧密分布的小颗粒大小纳米制剂,而避免例如样品污染和过度加热的缺点。 The system and method [0041] presented herein for controllably focusing acoustic, quickly and easily prepare a small particle size nanoformulations closely spaced, such as sample contamination and to avoid overheating drawbacks. 在一些实施方案中,可通过在合适的条件下使组合物的混合物经受声能聚焦区从而形成具有约IOnm至约50微米(例如,20nm至100nm、IOOnm至1微米、1微米至20微米)平均大小的颗粒来制备纳米制剂。 In some embodiments, can be obtained by the mixture composition is subjected to acoustic energy focal zone under suitable conditions to form having about IOnm to about 50 microns (e.g., 20 nm to 100nm, IOOnm to 1 micron, 1 micron to 20 microns) the average size of the particles to nanoformulation. 在一些情况下,将组合物的混合物在某些条件下暴露于聚焦声能,会大幅降低混合物中颗粒的平均大小。 In some cases, the composition of the mixture under certain conditions is exposed to the focused acoustic energy can significantly reduce the average size of the particles in the mixture. 在一些情况下,通过对组合物的混合物进行聚焦声处理来制备纳米制剂可涉及生产具有紧密分布的小颗粒,在混合物中没有已存在颗粒大小的大幅降低。 In some cases, a mixture prepared by the composition will be focused acoustic treatment nanoformulations relates to the production of small particles may have a tight distribution, with no significant reduction in the particle size of the mixture already present.

[0042] 本文中描述的混合物和/或纳米制剂的颗粒大小分布可使用动态激光光散射法(dynamic laser light scattering)(还称为光子相关光谱法(photon correlation spectroscopy))来测量(例如,使用Malvern Zetasizer-S,Zetasizer Nano ZS-9O 或Mastersizer2000 仪器;Malvern Instruments Inc. ;Southborough MA) 〇Malvern Zetasizer-S仪器用于使用在波长633nm运作的4mW He-Ne激光和雪崩光电二极管探测器(avalanche photodiode detector,APD)来评估平均颗粒大小。 [0042] The mixtures and / or nano-particle size formulations described herein may be distributed using a dynamic laser scattering (dynamic laser light scattering) (also called photon correlation spectroscopy (photon correlation spectroscopy)) is measured (e.g., using Malvern Zetasizer-S, Zetasizer Nano ZS-9O or Mastersizer2000 instrument; Malvern instruments Inc.; Southborough MA) 〇Malvern Zetasizer-S instrument for use in laser and 4mW He-Ne avalanche photodiode detector operating in the wavelength of 633nm (avalanche photodiode detector, APD) to evaluate the mean particle size. 可作为平均水动力大小(hydrodynamic size)来评估混合物中颗粒的平均大小。 As an average hydrodynamic size (hydrodynamic size) to evaluate the average size of the particles in the mixture. 颗粒大小分布可根据多分散指数(polydispersity index,F1DI)来评估,其在本领域中被认作是分布紧密性的量度。 The particle size distribution can be assessed according to the polydispersity (polydispersity index, F1DI), which is regarded as a measure of the tightness of the distribution in the art. 本文中讨论的混合物和纳米制剂的平均大小和PDI根据动态光散射国际标准(International Standard on dynamic light scattering) (IS013321)来计算。 The average size and PDI mixture and nano-formulations discussed herein is calculated based on a dynamic light scattering international standards (International Standard on dynamic light scattering) (IS013321).

[0043] 纳米制剂的颗粒可具有任何三维形状,例如球体、长方体、平行六面体、六面体、多面体等。 [0043] The nano-particles of the formulation may have any three-dimensional shape, such as spheres, rectangular, parallelepiped, hexahedral, polyhedral and the like. 应领会的是,本文中所用的术语"颗粒大小",可指通过本领域已知方法评估的估计的颗粒大小。 It should be appreciated that, as used herein, the term "particle size", may refer to the estimated evaluation methods known in the art of particle size. 例如,颗粒大小可指假设大致是球体形之颗粒的估计的直径。 For example, the particle size can refer to the estimated diameter substantially assume the ball shape of the particles. 或者,颗粒大小可指多面体(例如长方体)的估计的宽、长或其他维度。 Alternatively, particle size can refer to width, length, or other dimension polyhedron estimate (e.g., rectangular) is.

[0044] 聚焦声处理过程可根据本文中提供的系统和方法扩大规模。 [0044] The process can be focused acoustic system according to scale and methods provided herein. 在一些实施方案中, 处理容器可具有一个或更多个合适的入口和/或出口,其允许样品材料流入和流出容器。 In some embodiments, the processing vessel may have one or more suitable inlet and / or outlet which allows the sample material to flow into and out of the container. 一旦在容器中合适地放置,样品材料就在适当设置的条件下经受聚焦声处理。 Once properly placed in a container, it is subjected to a focused acoustic sample material under treatment conditions appropriately provided. 足够程度的聚焦声处理之后,样品材料可从容器中排出,以允许之前未被处理的更多样品经受聚焦声处理。 After a sufficient degree of focused acoustic treatment, the sample material may be discharged from the vessel, to allow more samples before subjecting the untreated focused acoustic treatment. 对于本文中描述的多个实施方案,可被认处理容器与处理室等同。 For the various embodiments described herein, it may be considered equivalent to the processing vessel and processing chamber.

[0045] 在一些实施方案中,声处理系统可包括储池(reservoir)和处理室(process chamber),各自具有入口和出口,其彼此之间流体连通;即,允许流体通过合适的导管在储池与处理室之间移动(travel)。 [0045] In some embodiments, the sound processing system may include a reservoir (Reservoir) and a processing chamber (process chamber), each having an inlet and an outlet, in fluid communication with one another; i.e., through a suitable conduit to allow fluid in the reservoir moving the processing chamber between the reservoir and the (travel). 因此,可引起来自储池的样品材料移动至处理室,用于在合适的条件下进行聚焦声处理,随后可引起移动回至储池。 Thus, the sample can cause material from the reservoir is moved to the processing chamber for focusing acoustic treatment under appropriate conditions, can cause then moved back to the reservoir. 结果,样品材料可周期式地被声处理,其中一部分样品材料可接受多次聚焦声处理。 As a result, sample material may be sonicated for periods of formula, wherein the portion of the sample material acceptable focused acoustic processing times.

[0046] 在一些实施方案中,样品材料可从供给储池移动至用于聚焦声处理的处理室。 [0046] In some embodiments, the sample may be material to the processing chamber for supplying focused acoustic processing moves from the reservoir. 被处理的样品材料可随后从处理室移动至与供给储池隔开的不同容器。 Sample material to be treated may then be moved from the processing chamber to the supply reservoir spaced from the different containers.

[0047] 在一些实施方案中,样品材料可从供给储池移动通过用于不同水平处理(例如不同条件的聚焦声)的多个处理室。 A plurality of processing chambers [0047] In some embodiments, the sample material may be moved from the supply reservoir through a different processing levels (e.g. focused acoustic different operating conditions). 还可提供额外的导管用于样品材料的添加/移除。 Additional conduits may also be provided for the sample material is added / removed.

[0048] 图1举例说明了根据美国专利No. 6, 948, 843 ;6, 719, 449和7, 521,023描述的系统的聚焦声处理系统10。 [0048] FIG 1 illustrates U.S. Patent No. 6, 948, 843 according to; focused acoustic processing system described system 6, 719, 449 and 7, 521,023 10. 所述系统利用压电式换能器20产生朝向容器40所限定之空间内的样品42的声能波22。 42 sound samples in the space of the system by the piezoelectric transducer 20 generates 40 towards the container 22 defining the energy waves. 容器40位于流体浴容器30内,声耦合介质32 (例如,水)位于其中并与容器的外表面相接触。 Fluid bath container 40 is located within the container 30, the acoustic coupling medium 32 (e.g., water) positioned therein and in contact with the outer surface of the container. 声能波22从换能器20传送通过介质32,穿过容器40的壁并在容器壁内或与其接近的聚焦区24会聚。 Acoustic energy wave 22 transmitted from the transducer 20 through the medium 32, through the wall of the vessel 40 and the vessel wall or close to the focal zone 24 converges. 声波的频率可具有任何合适的范围,例如约100 千赫至约100兆赫,或约500千赫至约10兆赫。 Frequency sound waves may have any suitable range, such as from about 100 kHz to about 100 MHz, or from about 500 kHz to about 10 MHz. 聚焦区24与样品42邻近,从而向样品42 施用非接触式等温机械能。 Focal zone 24 adjacent to the sample 42, sample 42 so as to be administered non-contact type isothermal mechanical energy. 聚焦区可具有任何合适的形状和大小,例如具有小于约2cm的宽度(例如,直径)。 Focal zone may have any suitable shape and size, for example having a width of less than about 2cm (e.g., diameter).

[0049] 本发明人已认识并领会到,用聚焦声系统的样品材料的处理过程扩大规模为更大体积的材料的处理是有利的。 [0049] The present inventors have recognized and appreciated that, during processing to scale with the treated sample material focused acoustic system for larger volume of material is advantageous. 虽然图1的系统可包含允许换能器与容器之间的相对运动的机械和/或电机构(mechanism),但样品材料通常包含在容器40所限定的空间内。 While the system of FIG. 1 may comprise allowing mechanical and / or electrical transducer means relative movement between the transducer and the container (mechanism), but typically the sample material contained within the space defined by the container 40. 同样, 为处理随后的样品材料,换能器和/或容器应被移开。 Similarly, for the subsequent treatment of the sample material, transducer and / or containers to be removed. 图2描述允许样品材料流入和流出的声处理系统1〇,其无需移动换能器20或容器50。 2 depicts allow sample material to flow into and flow out of the system sonicated 1〇 that without moving the transducer 20 or the container 50. 图2的系统与图1所示系统相似,其包括具有样品材料52位于其中的容器50 ;但是,系统还包括样品来源60和样品排出装置(drain) 70。 The system shown in FIG. 1 system similar to FIG. 2, which comprises a sample material 52 having located therein a container 50; however, the system further includes a sample source 60 and a sample discharging means (drain) 70. 容器50包括与导管64流体连通的入口62,以允许来自来源60的样品材料的流入,沿着箭头A的方向穿过导管64进入容器50。 Container 50 comprises inlet 62 in fluid communication with the duct 64, to allow the sample material flows from source 60 along the direction of arrow A through the conduit 64 into the container 50. 容器还包括出口72,其允许来自容器的样品材料流出,并沿着箭头B的方向进入导管74,这提供样品材料至排出装置70的流体流动。 The container further comprises an outlet 72, which allows the sample material flows out from the container and into conduit 74 along the direction of arrow B, which provides a fluid flow of sample material to the discharge device 70. 因此,该系统提供未处理样品材料移动到容器中、被聚焦声能处理并继而移动出容器的能力,这允许更多样品材料被聚焦声处理而不需要容器或换能器彼此相对运动。 Thus, the system provides an untreated sample material into containers, the focused acoustic energy and then moved out of the processing capacity of the container, which allows for more focused sample material without the need for acoustic treatment vessel or transducer relative to each other.

[0050] 图3描述了聚焦声处理系统100的另一个举例说明性实施方案,其使得用聚焦声处理样品材料的规模扩大方法成为可能。 [0050] FIG 3 depicts another focused acoustic processing system 100 illustrative embodiment, a method which makes scale sonication with a focused sample material becomes possible. 系统还提供多次处理样品材料的能力。 The system also provides the ability to process multiple sample material. 系统包括用于容纳样品材料供给的储池120和提供用于样品材料经受声处理之空间的处理室110。 The system includes a sample receiving feed material reservoir chamber 120 and provides a sample material is subjected to the processing space 110 of the acoustic treatment. 储池120包括允许样品材料流入至储池和从储池流出的储池出口122和储池入口124。 Reservoir 120 comprises a material allowing the sample to flow into the reservoir and an outlet from the reservoir 122 and reservoir inlet 124 flowing out of the reservoir. 相似地,处理室110包括允许样品材料流入至处理室和从处理室流出的室入口112和室出口114。 Similarly, the processing chamber 110 includes allowing the material to flow into the sample chamber to the process chamber and flowing out of the inlet chamber from the processing chamber 112 and outlet 114. 储池出口122允许样品材料沿着箭头C的方向从储池移动进入导管130,并进一步通过室入口112移动进入处理室。 Reservoir outlet 122 allowing the sample material from the reservoir into the catheter 130 is moved along the direction of arrow C, and further into the processing chamber 112 to move through the chamber inlet. 在样品材料的充分声处理后,适当量的样品材料可通过室出口114从处理室离开,进入导管140,从而沿着箭头D的方向通过储池入口124移动回到储池120中。 After sufficient sample material processing sound, an appropriate amount of sample material 114 can exit through the outlet chamber from the processing chamber into the conduit 140, whereby the direction of arrow D by moving the reservoir 124 back to the inlet reservoir 120.

[0051] 因此,与处理室的空间所限定的体积相比,更大量的样品材料可被声处理。 [0051] Accordingly, compared with the volume of the space defined by the processing chamber, a greater amount of sample material may be sonicated. 此外, 样品材料可被多次声处理,这是因为从处理室运送回储池的已处理材料,可最终引起从储池移动回到处理室用于进一步的声处理。 Furthermore, the sample material may be sonicated several times, because this is transported from the processing chamber back to the reservoir of the processed material, may ultimately cause movement back from the reservoir chamber for further processing sonication.

[0052] 如本文中所描述的,可提供任何合适的结构作为入口和/或出口。 [0052] As described herein, any suitable structure may be provided as an inlet and / or outlet. 例如,合适的入口和出口可包括喷嘴(nozzle)、孔、管、导管等。 For example, suitable inlet and outlet may comprise a nozzle (Nozzle), hole, tube, catheter or the like. 在一些情况下,入口和/或出口可包括装有阀的结构,当期望时其开放和关闭以控制材料的流入和流出。 In some cases, the inlet and / or outlet may comprise a valve provided with a structure, when it is desired to open and close to control the inflow and outflow of material. 此外,处理室和储池不限制入口/出口的数目和位置。 Further, the processing chamber and the reservoir is not limited inlet / outlet number and position. 例如,处理室和/或储池可具有额外的入口或出口,用于使样品材料流动至在导管130、140旁的其他合适位置。 For example, the processing chamber and / or the reservoir may have additional inlet or outlet for the sample material to flow into other suitable locations next to the conduit 130, 140.

[0053] 可提供任何合适的动力用于引起样品材料在储池与处理室之间的运动(例如,穿过导管130、140和各自的入口/出口)。 [0053] Any suitable power may be provided for causing movement of sample material between the reservoir and the processing chamber (e.g., through the catheter 130, 140 and respective inlet / outlet). 在一些实施方案中,提供泵150以对样品材料加压,以使样品材料从储池移动到处理室并返回。 In some embodiments, pump 150 to provide pressurized material sample to move the sample material from the reservoir and returns to the process chamber. 可使用任何合适的泵装置。 Any suitable pump means. 在一些情况下, 泵与导管偶联,例如图3所示在导管140与泵150之间的偶联。 In some cases, coupling of the pump to the catheter, as shown in FIG. 3, for example, coupling between the conduit 140 and the pump 150. 可在系统的任何合适位置提供一个或更多个合适的泵。 It may provide one or more suitable pump system at any suitable location. 在一些实施方案中,无需泵装置,在系统的多个区域之间提供压差梯度。 In some embodiments, no pump means for providing a plurality of pressure gradient between the area of ​​the system. 例如,可沿着导管130保持压力梯度,从而引起样品材料从储池通过储池出口122 并通过室入口122进入处理室的流动。 For example, a pressure gradient may be maintained along the conduit 130, thereby causing the sample material from the reservoir 122 and flows into the processing chamber through the chamber inlet 122 through the reservoir outlet. 相似地,还可沿着导管140保持压力梯度,其引起样品材料从处理室通过室出口114,通过导管140并通过储池入口124进入储池的流动。 Similarly, also maintain pressure gradient along the conduit 140, which causes the sample material from the process chamber through the chamber outlet 114, through conduit 140 and into the reservoir through the reservoir inlet 124 flows.

[0054] 图4示出聚焦声处理系统200的另一个举例说明性实施方案,其使样品材料的大规模聚焦声处理成为可能。 Another [0054] FIG. 4 shows a focused acoustic processing system 200 of the illustrative embodiment, which make mass focused acoustic sample material processing possible. 该系统提供样品材料通过处理室的单通道。 The system provides a single-channel sample material through the process chamber. 所述系统包括:保存待处理样品材料之供应的第一储池220、提供用于样品材料经受声处理之空间的处理室210和用于接收已处理之样品材料的第二储池230。 The system comprising: a first storage reservoir 220 to be processed of the sample material supply, there is provided a sample material is subjected to the processing chamber space 210 and the acoustic treatment of the treated material for receiving a sample of a second reservoir 230. 第一储池220包含储池出口222,以允许样品材料从储池沿着箭头E的方向进入导管240的流出。 The first reservoir 220 includes a reservoir outlet 222 to allow the outflow conduit 240 into the sample material from the reservoir along the direction of arrow E. 处理室210包含室入口212,其允许样品材料进入处理室的流入。 The processing chamber 210 comprises an inlet chamber 212, which allows the inflow of the sample material into the process chamber. 处理期间,声换能器202产生声波204以形成合适的聚焦区206,样品材料暴露于其中。 During processing, the acoustic transducer 202 generates an acoustic wave 204 to form a suitable focal zone 206, wherein the sample material is exposed. 当样品材料被充分处理后,合适量的样品材料可从处理室离开,通过室出口214并进入导管250,从而沿着箭头F的方向移动并通过储池入口232进入第二储池230。 When the sample material to be adequately processed, an appropriate amount of sample material may exit from the processing chamber through the chamber outlet 214 and into conduit 250, so as to move along the direction of arrow F and into the second reservoir 230 via reservoir inlet 232. 如图3所提供的,虽然与处理室之体积所限定的样品材料量相比更大量的样品材料可在该系统中被声处理,但是样品材料的流动实际上不是循环的。 3 is provided, although the volume of sample material compared to the amount of the processing chamber defined by a greater amount of sample material can be sonicated in the system, but in fact, the flow of sample material is not cyclic.

[0055] 与关于图3的如上所述相似,可提供任何合适的动力以引起样品材料从第一储池220移动至处理室210,并从处理室移动至第二储池230。 [0055] Similar to as described above with respect to FIG. 3, any suitable power can be provided to cause movement of the sample material from the first reservoir 220 to the processing chamber 210, and the processing moves from the second chamber to the reservoir 230. 在一些实施方案中,提供泵260以迫使样品材料移动通过聚焦声处理系统。 In some embodiments, there is provided a pump 260 to force movement of the sample material through the focused acoustic processing system. 如图4所示(非限制性地),泵260可与导管(例如,非限制性地,导管250)相偶联并被合适地操作。 As illustrated (without limitation), the pump 260 may be (e.g., without limitation, the catheter 250) and is coupled with the conduit 4 and to operate properly.

[0056] 图5描述了聚焦声处理系统300的一个举例说明性实施方案,其提供样品材料的大规模聚焦声处理,在其中采用了多个处理室。 [0056] FIG 5 depicts an illustrative embodiment of the focused acoustic processing system 300, which provide large-scale focused acoustic treatment of the sample material, in which a plurality of process chambers employed. 图示的系统允许样品材料穿过每个处理室, 在其中样品材料可经受相似或不同的聚焦声处理条件。 The illustrated system allows the sample material to pass through each processing chamber in which the sample material can be subjected to a focused acoustic similar or different processing conditions. 此外,如所期望的,可在处理室之间添加或移除一部分样品材料。 Further, as desired, to add or remove a portion of sample material between the process chamber.

[0057] 储池330保存待在第一处理室310和第二处理室320中处理的样品材料的供应, 每个处理室均为样品材料提供经受聚焦声处理的空间。 [0057] The reservoir 330 serves to stay in the first process chamber to save material sample processing chamber 310 and the second handle 320, each processing chamber are subjected to a sample material to provide a focused acoustic spatial processing. 储池330包括储池出口332,其允许样品材料从储池的流出,并沿着箭头G的方向进入导管340。 Reservoir outlet 330 includes a reservoir 332, which allows the sample material flows from the reservoir and into the catheter 340 in the direction of arrow G. 处理室310包含室入口312, 其允许样品材料的流入处理室。 The processing chamber 310 comprises a chamber inlet 312, which flows into the processing chamber to allow sample material. 声处理期间,换能器302提供声波304以形成合适的聚焦区306,样品材料暴露于其中。 During sonication, transducer 302 provides acoustic wave 304 to form a suitable focal zone 306, wherein the sample material is exposed. 在样品材料被充分声处理后,合适量的样品材料可从处理室离开,通过室出口314并进入导管350。 After the sample material to be treated sufficiently sound, a suitable amount of sample material may exit from the processing chamber, through the chamber 314 and into the outlet conduit 350. 样品材料可沿着箭头I的方向移动并通过室入口322最终进入第二处理室320。 Sample material can be moved in the direction of arrow I in 322 and eventually into the process chamber 320 through the second chamber inlet. 样品材料可在与第一处理室310相同或不同的条件下在第二处理室320所限定的空间中经受进一步声处理。 Sample material may be subjected to further processing in the acoustic space of the second process chamber 320 defined in the first process chamber 310 with the same or different conditions. 换能器303产生声波305,形成合适的聚焦区307,其可用于样品材料的声处理。 303 generates an acoustic wave transducer 305, formed of suitable focal zone 307, which may be used for acoustic treatment of the sample material. 合适的声处理后,样品材料可通过室出口324流出第二处理室320,并沿着箭头K的方向运动进入导管360,用于在排出装置362收集。 After suitable sonication, the sample material through the chamber outlet 324 out of the second processing chamber 320, and into conduit 360 in the direction of arrow K, the means 362 for collecting discharged.

[0058] 在一些实施方案中,如图5所示,提供泵380以提供动力来引起样品材料移动通过聚焦声处理系统。 [0058] In some embodiments, as shown in FIG. 5, there is provided a pump 380 to provide power to cause movement of the sample material by a focused acoustic treatment system. 虽然泵380被描述为与导管340偶联,可领会的是,可在任何合适的位置将任何合适的泵与聚焦声处理系统相偶联。 Although the pump 380 is described as being coupled with the conduit 340, can be appreciated, any suitable pump coupled with focused acoustic processing system at any suitable location.

[0059] 可在系统中合适的位置提供导管370、372,从而允许按需求被添加和/或移除样品材料。 [0059] 370, 372 may be provided in a catheter system suitable location, thereby allowing the request to be added and / or removed sample material. 例如,由于样品材料沿着导管340朝向第一处理室310流动,导管370可提供与样品材料一起在处理室310中待声处理的添加成分(例如,药物、载体表面活性剂等)。 For example, since the sample material to flow toward the first process chamber 310 along the conduit 340, the conduit 370 may provide additional components to be processed in the processing chamber 310 sound with the sample material together (e.g., pharmaceutical agents, carriers surfactants, etc.). 相似地,导管372还可移出或提供额外的成分,其可在处理室320中与样品材料一起被声处理。 Similarly, the conduit 372 may be removed or to provide additional ingredients which can be sonicated in the processing chamber 320 together with the sample material. 方向箭头H、J用以例示导管370、372可视情况而用来添加或移出材料。 The direction of arrow H, J to illustrate the catheter 370, 372 may optionally be added to or removed from the material. 可以领会的是,任何聚焦声处理系统可视情况而提供某些位置,在其中样品材料可用额外的成分补充或在其中可从处理系统中移出部分样品材料。 It is appreciated that any focused acoustic processing system may optionally be provided in certain locations, in which the sample material may be additional ingredients or supplements in which the portion of the sample material can be removed from the processing system.

[0060] 在一些实施方案中,本文中描述的聚焦声处理系统可包括合适的代偿控制系统, 用于感知声样品处理的特征并根据所感知的特征来调整系统的参数。 [0060] In some embodiments, focused acoustic processing system described herein may comprise suitable compensatory control system for sensing the acoustic characteristics of a sample processing system and adjusting the parameters in accordance with the sensed characteristic. 例如,可监测样品材料的某特性,例如,样品材料的颗粒大小分布、在样品材料中的平均颗粒大小、在沿处理系统之多个位置处的样品材料体积、样品材料移动通过系统的速率或任何其他合适的特征。 For example, one can monitor the characteristics of the sample material, e.g., the particle size distribution of the sample material, the average particle size of the sample material, the sample material at a plurality of positions along the volume of the processing system, the sample material moves through the system or the rate of any other suitable features. [0061] 例如,经受通过两个处理室中第一个的声处理后,系统可能感知到样品材料的平均颗粒大小比在那时期望的平均颗粒大小更大。 [0061] For example, subjected to post-treatment chamber by two first acoustic treatment, the system may be perceived to an average particle size an average particle size larger than the sample material in a desired time. 结果,可据此调整第二处理室中样品材料的声处理(例如,处理可被延长,从换能器输出的功率可被提高,等)。 As a result, the sample can be adjusted accordingly sonicated material in the second process chamber (e.g., process may be extended, the power output from the transducer can be improved, and the like). 或者,可期望样品材料中90%的颗粒应在某个大小范围内,并且测定了(由计算机或使用者监测大小范围)样品材料90%的颗粒在处理期间的那时小于优选的大小范围。 Alternatively, the sample material may be desirable 90% of the particles should be within a certain size range, and determining the size range during (or by the computer user to monitor the size range) of 90% of the particles of the sample material in the processing time of less than preferred. 因此,可据此调整处理参数,以使样品材料经受缩短的处理时间,导致在样品材料中颗粒大小之降低的总体降低。 Thus, the processing parameters can be adjusted accordingly, so that the sample material to shorten the processing time, resulting in an overall decrease in reduction of the particle size of the sample material. 或者,可以测定,为合适地形成脂质体或微团以包封生物活性剂,在样品材料中提供了不足量的表面活性剂。 Alternatively, can be determined, a suitable form of liposomes or micelles to encapsulate biologically active agents, provides an insufficient amount of surfactant in the sample material. 因此,可将额外的表面活性剂注入(例如,通过导管370、372)样品材料中,从而可适当地形成脂质体/微团。 Therefore, the additional surfactant is injected (e.g., via a conduit 370, 372) the sample material, which can be suitably formed liposome / micelle. 还可监测样品材料的其他特征,产生对处理参数的合适调整。 Other features may also monitor the sample material, generate the appropriate adjustments to the processing parameters. [0062] 例如,当组合物混合物中已存在的颗粒的大小降低时,在混合物中颗粒的平均起始大小范围可以是约10微米至约500微米,且在合适的条件下将所述混合物暴露于聚焦声能后,所产生的混合物中颗粒的平均大小的范围可以是,例如10微米至50微米,或IOnm至100nm。 [0062] For example, when reducing the size of the composition was already present in the mixture of particles, the average particle size range in the starting mixture may be from about 10 microns to about 500 microns, and the mixture was exposed under appropriate conditions after the focused acoustic energy, the range of the average size of the particles in the resulting mixture may be, for example, 10 to 50 microns, or IOnm to 100nm. 在颗粒大小降低的另一个实例中,混合物中具有15mL至20mL体积(包括药物,例如布洛芬)之颗粒的平均起始大小可以是约200微米。 In another example of particle size reduction, the mixture having a volume of 15mL to 20mL (including drugs, such as ibuprofen) the average starting size of the particles may be about 200 microns. 将所述混合物暴露于在约150W功率、具有约IMHz频率的声能的聚焦区10分钟后,混合物中颗粒的平均大小可降低至约40 微米。 After exposing the mixture to about 150W of power, having a focal zone of approximately IMHz frequency acoustic energy for 10 minutes, the average size of the particles in the mixture may be reduced to about 40 microns. 将混合物暴露于同样的聚焦声条件小于1小时(例如,30分钟)后,混合物中颗粒的平均大小可降低至小于l〇〇nm。 The focused acoustic exposing the mixture to conditions similar less than 1 hour (e.g., 30 minutes), the average size of the particles in the mixture may be reduced to less than l〇〇nm. 提高混合物向聚焦声条件的暴露可产生具有甚至更小的平均颗粒大小的混合物。 The mixture may increase even produce a mixture having a smaller average particle size is exposed to the focused acoustic conditions. 在一些实施方案中,将具有治疗组合物和载体组合物两者的混合物暴露于聚焦声能,可导致在混合物中颗粒受控地降低至混合物中颗粒平均起始大小的低至0. 01 %的百分比(例如,从200微米的平均大小至IOnm的平均大小)。 In some embodiments, a mixture of both the therapeutic composition and the carrier composition is exposed to a focused acoustic energy, can cause the particles to a controlled reduced to as low as 0.01% the starting mixture the average particle size in the mixture percentage (e.g., an average size from IOnm to 200 microns average size).

[0063] 本文中描述的混合物可例如以纳米制剂前体的形式包含数种组合物,或所述混合物可以是纳米制剂本身。 [0063] The mixture described herein may comprise, for example, several compositions in the form of pre nanoformulation body, or the mixture may be nano-formulation itself. 在一些情况下,在混合物或纳米制剂中的一种或更多种组合物可以是任何药物、营养品、药用化妆品或其组合。 In some cases, in a mixture or one or more nano-formulation of the compositions may be any pharmaceutical, nutraceutical, cosmeceutical, or a combination thereof.

[0064] 药物可用作混合物中的生物活性组合物,并可包括但不限于:选择性雌激素受体调节剂(selective estrogen receptor modulator,SERM)(例如,他莫昔芬)、烧化剂(例如,取代的咪唑化合物(例如达卡巴嗪))、紫杉烷化合物(例如,紫杉醇)、核苷类似物(例如,吉西他滨)、他汀类(例如,洛伐他丁、阿托伐他汀、辛伐他汀,等)、嘧啶类似物(例如, 5_氟尿嘧啶)、核酸分子(例如,DNA、RNA、mRNA、siRNA、RNA干扰分子、质粒,等)、药物(例如,布洛芬、桂利嗪、吲哚美辛、灰黄霉素、非洛地平、槲皮素,等)等。 [0064] The mixture of the drug useful biologically active composition, and may include, but are not limited to: selective estrogen receptor modulators (selective estrogen receptor modulator, SERM) (e.g., tamoxifen), burnt agent ( For example, substituted imidazole compounds (e.g., dacarbazine)), taxane compounds (e.g., paclitaxel), nucleoside analogs (e.g., gemcitabine), statins (e.g., lovastatin, atorvastatin, suberic atorvastatin, etc.), pyrimidine analogs (e.g., fluorouracil 5_), a nucleic acid molecule (e.g., DNA, RNA, mRNA, siRNA, RNA interference molecules, plasmids, etc.), drugs (e.g., ibuprofen, Cinnarizine , indomethacin, griseofulvin, felodipine, quercetin, etc.) and so on. 在本文所述纳米制剂中可包含任何合适的药物。 The nano-formulation herein may comprise any suitable pharmaceutical.

[0065] 如讨论的那样,纳米制剂中的组合物可包含多核苷酸分子(例如,siRNA、RNA、 DNA、质粒)或多肽化合物。 [0065] As discussed, nano-formulation composition may comprise a polynucleotide molecule (e.g., siRNA, RNA, DNA, a plasmid) or a polypeptide compound. 根据一些实施方案,可制备包含siRNA或其他多核苷酸的纳米制剂而不使siRNA分子降解,或至少不使SiRNA或其他分子显著降解。 According to some embodiments, can comprise preparing siRNA or other nanoformulations polynucleotide without causing the degradation of siRNA molecules, or at least not to SiRNA molecules or other significant degradation. 即,作为纳米制剂的一部分而提供的包含siRNA分子的组合物通常保留siRNA分子调节相应mRNA分子或其他靶标化合物之活性方面的功能,从而具有对蛋白质表达或靶标之其他功能的整体作用。 I.e., as part of the nano-formulation provided a composition comprising a siRNA molecule is usually reserved siRNA molecule regulation activity of the corresponding mRNA molecule or other target compound of the target areas, so as to have on protein expression or overall effect of other functional targets of. 所述多核苷酸或多肽化合物可以是针对靶标的反义化合物。 The compounds polynucleotide or polypeptide may be a target for an antisense compound. 在mRNA的情况下,可能被干扰的一些功能包括mRNA向蛋白质翻译位置的转位、蛋白质从mRNA的实际翻译、mRNA的剪接以产生一种或更多种mRNA种类、mRNA的周转或降解以及RNA可参与的可能的独立催化活性。 In the case of mRNA, some features may be interfered with include translocation of mRNA to protein translation position, actual translation of protein from the mRNA, mRNA splicing to yield one or more mRNA species, or degradation of the mRNA turnover and RNA may be involved in the independent catalytic activity. 对mRNA功能的此类干扰的整体作用可表现为调节一种或更多种蛋白质的表达,这可导致基因表达的升高(刺激)或降低(抑制)。 The overall effect of such interference with mRNA function can be expressed as an expression regulating or more proteins, which can lead to increased gene expression (stimulation) or a decrease (inhibition).

[0066] 本发明人已认识到,与用于生产包含siRNA或其他多核苷酸的纳米制剂的不使用聚焦声的方法引起多核苷酸化合物的降解,例如,因为在处理纳米制剂期间向化合物引入的机械剪切、压力、异物污染和/或加热。 [0066] The present inventors have recognized that, without the use of focused acoustic method for the production of the nano-formulations comprising siRNA or other polynucleotide cause degradation of the polynucleotide compound, e.g., as introduced into the compound during processing nanoformulation mechanical shear, pressure, contamination with foreign matter and / or heat. 使用聚焦声制备的包含siRNA或其他多核苷酸化合物的纳米制剂可具有更高的效力或其他性能,例如,因为在处理纳米制剂期间引入到材料中的更低的热量,以及所引入的降低的机械剪切、压力和/或污染物。 Prepared using focused acoustic comprising a siRNA or a polynucleotide nanoformulations other compounds may have a higher efficacy or other properties, e.g., because during the processing nanoformulation heat introduced into the lower material and the introduced reduction mechanical shear, pressure and / or contaminants. 例如在siRNA的情况下,分子相对不稳定,并在未灭菌环境和升高的温度水平中核酸酶的影响下发生降解。 For example, in the case of siRNA, relatively unstable molecules, and degraded under the influence of non-sterile environment and elevated temperature levels in nucleases. 用于生产含有siRNA之纳米制剂的聚焦声处理试图控制siRNA的温度敏感性。 For the production of focused acoustic nanoformulations containing siRNA attempt to control the process temperature sensitivity of the siRNA. 因此,本文中描述的一些方面可使得能够生产具有治疗或其他功能性效力的包含siRNA或其他多核苷酸材料的纳米制剂,这对于其他处理来说是根本不可能的。 Accordingly, some aspects may be described herein enables the production of nano-formulation with therapeutic efficacy, or other functional siRNA or other polynucleotides comprise materials, which other processing is impossible.

[0067] 混合物中至少一种组合物可包含治疗剂,混合物中一种或更多种其他组合物可包含非治疗剂。 [0067] The mixture may be at least one composition comprising a therapeutic agent, a mixture of one or more other compositions may contain a non-therapeutic agent. 在一些实施方案中,混合物中的组合物可包含可用于包装混合物中其他组合物(例如,治疗剂)的载体化合物。 In some embodiments, the mixture may comprise a composition that can be used in other packaging mix composition (e.g., therapeutic agent) a carrier compound. 在一些情况下,混合物可包含表面活性剂,其可起到降低混合物中液体表面张力(例如在两种液体间的界面张力或在液体和固体间的张力)的作用。 In some cases, the mixture may include a surfactant, which may serve to reduce the surface tension of the liquid mixture (e.g., interfacial tension between two liquids or between a liquid and a solid tension) is. 表面活性剂可包括一种或更多种具有疏水和亲水两种基团的两亲性分子。 Surface active agents may comprise one or more amphiphilic molecules having two kinds of hydrophobic and hydrophilic groups. 合适的表面活性剂可以是阴离子性的,例如,具有以下至少一个:硫酸盐(例如,月桂基硫酸铵、月桂基硫酸钠、十二烷基硫酸钠、月桂醇聚醚硫酸钠(sodium laureth sulfate)、肉豆蘧醇聚醚硫酸钠(sodium myreth sulfate))、磺酸盐(sulfonte)(例如,磺基琥拍酸二辛酯钠、全氟辛烷磺酸盐、全氟丁烷磺酸盐、烷基苯磺酸盐)、磷酸盐(例如,烷基芳基醚磷酸盐、烷基醚磷酸盐)或羧酸盐基团(烷基羧酸盐、硬脂酸钠、月桂酰肌氨酸钠、全氟壬酸盐、全氟辛酸盐)。 Suitable surfactants may be anionic, e.g., having at least one of the following: sulfates (e.g., ammonium lauryl sulfate, sodium lauryl sulfate, sodium lauryl sulfate, sodium laureth sulfate (sodium laureth sulfate ), myristoyl Qu laureth sulfate (sodium myreth sulfate)), sulfonate (sulfonte) (e.g., dioctyl sulfo sodium succinate Sign ester, perfluorooctanesulfonate, perfluorobutanesulfonate salts, alkylbenzene sulfonate), phosphates (e.g., alkyl aryl ether phosphates, alkyl ether phosphates) or carboxylate groups (alkyl carboxylate, sodium stearate, lauroyl muscle acid sodium, salts perfluorononanoate, perfluorooctanoate). 在一些实施方案中,表面活性剂可以是阳离子性的、两性离子性的或非离子性的。 In some embodiments, the surfactant may be cationic, non-ionic zwitterionic.

[0068] 在一些实施方案中,本公开内容的纳米制剂可制备为乳剂(例如,纳米乳剂),其可包含分散介质,例如水性介质或油基介质。 [0068] In some embodiments, the nano-formulations of the present disclosure may be prepared as an emulsion (e.g., nanoemulsions), which may contain a dispersion medium such as an aqueous medium or an oil-based medium. 在一个实施方案中,油基介质选自但不限于: 来自植物和海洋来源的饱和及不饱和油、硅油、矿物油和植物来源的油。 In one embodiment, the oil-based medium is selected from but not limited to: saturated and unsaturated oils, silicone oils, mineral oils, and oils derived from plants and plant-derived marine origin. 表面活性剂(如果包含的话)可以是任何离子(例如,阴离子、阳离子)性、非离子性或两性离子性材料。 Surfactant (if included) may be any ionic (e.g., anionic, cationic), nonionic or zwitterionic materials. [0069] 在一些实施方案中,将混合物暴露于聚焦区可包括在等温环境中处理混合物。 [0069] In some embodiments, exposing the mixture to the focal zone may comprise treating the mixture in an isothermal environment. 因为向混合物施用的聚焦声能不具有显著程度的随机散射能(即,以热形式),所以样品材料的温度可通常保持在合适程度的变化之内。 Since focused acoustic energy applied to the mixture does not have a significant degree of random scattering ability (i.e., in the form of heat), the temperature of the sample material may be generally maintained within suitable degree of change. 例如,混合物的温度可保持在起始温度的约5°C 内、约2°C内或约1°C内的温度。 For example, the temperature of the mixture may be maintained at the starting temperature of about 5 ° C, a temperature within about 2 ° C or within approximately 1 ° C.

[0070] 根据本文中所描述方法制备的纳米制剂可具有任何合适的颗粒大小分布。 [0070] The herein described formulations prepared according to the method of nano may have any suitable particle size distribution. 在一些实施方案中,虽然不是必需的,但是所描述的涉及使用聚焦声能以制备纳米制剂的系统和方法导致了单峰的颗粒大小分布。 In some embodiments, although not required, but the described involves the use of focused acoustic energy leads unimodal particle size distribution system and method for preparing nano formulation. 例如,颗粒大小分布可与高斯分布(Gaussian distribution)相似。 For example, particle size distribution with a Gaussian distribution (Gaussian distribution) is similar. 但是,在另一些情况下,合适的纳米制剂的颗粒大小分布是多峰的。 However, in other cases, the particle size distribution suitable nanoformulations is multimodal. 在一些实施方案中,经声处理的纳米制剂的颗粒大小分布的PDI小于0. 5,小于0. 3,小于0. 1,小于0. 08或小于0. 06。 In some embodiments, PDI the particle size by sonication nanoformulations distribution of less than 0.5, less than 0.3, less than 0.1, less than 0.08 or less than 0.06. 例如,经合适声处理的纳米制剂的颗粒大小分布的PDI可在约0. 03至约0. 1之间、约0. 05至约0. 09之间或约0. 06至约0. 08之间。 For example, PDI the particle size by sonication nanoformulation suitable distribution may be between about 0.03 to about 0.1, between about 0.05 to about 0.09 or from about 0.06 to about 0.08 of between. 在一些实施方案中,经声处理的纳米制剂的颗粒大小分布的相对标准偏差可以是所述纳米制剂的平均颗粒大小的小于1%,小于〇. 5%或在其0. 1%至0.8%之间。 In some embodiments, the relative standard deviation of the particle size distribution of nano-preparation sonication may be an average particle size of less than 1% nanoformulation, square less than 5%, or in which 0.1 to 0.8% between.

[0071] 如本文中讨论的,颗粒大小分布可以以特定阈值大小之上或之下的颗粒数目的形式来表示。 [0071] As discussed herein, the particle size distribution may be represented in a number of particles above or below a certain threshold size form. 多个颗粒的d90颗粒大小指90%的颗粒具有比所给定的d90大小更大的大小。 Plurality of particles of a particle size d90 means that 90% of the particles have a d90 than the given magnitude larger size. 例如,具有10微米d90颗粒大小的多个颗粒被定义为90%的颗粒具有比10微米更大的大小。 For example, the plurality of particles have a d90 particle size of 10 [mu] m is defined as 90% of the particles have a size greater than 10 microns. 因此,同样的例子,10%的颗粒具有小于10微米的大小。 Thus, the same example, 10% of the particles have a size less than 10 microns. 多个颗粒的d50颗粒大小指50%的颗粒具有比所给定的d50大小更大的大小,即中值。 Plurality of particles of a particle size d50 means than 50% of the particles have a size d50 given larger size, i.e. a median. 多个颗粒的dlO颗粒大小指10% 的颗粒具有比所给定的dlO大小更大的大小。 A plurality of particles of a particle size dlO means than 10% of the particles have a size given dlO larger size. 通常,本文中讨论的d90、d50和dlO颗粒大小的测量针对基本上单峰的颗粒大小分布。 Typically, measurements discussed herein d90, D50 and dlO particle size distribution for the particle size of substantially unimodal.

[0072] 使用本公开内容的聚焦声能制备的纳米制剂的保质期可比使用常规技术制备的制剂的保质期更长。 Nanoformulation shelf life [0072] The present disclosure using focused acoustic energy produced than the shelf life of formulations prepared using conventional techniques longer. 在一些实例中,当在周围环境中贮存时,混悬剂、乳剂或某些载体制剂(例如,包封生物活性剂的脂质体或微团)的颗粒可具有聚集成更大颗粒的趋势,表现出相对短的保质期的颗粒大小分布。 In some examples, when stored in an ambient environment, suspensions, emulsions, or some vector preparations (e.g., encapsulating a bioactive agent in liposomes or micelles) of the particles may have a tendency to aggregate into larger particles , exhibit a relatively short shelf life of the particle size distribution. 例如,在脂质体或微团颗粒的情况下,邻近颗粒的磷脂分子可组合在一起,导致混合物中平均颗粒大小的整体提高。 For example, in the case of a liposome or micelle particles, the particles adjacent phospholipid molecules may be combined together, resulting in an overall increase in the average particle size of the mixture. 或者,在常规混合物中的颗粒可具有随时间降解(即,失去功能)的趋势。 Alternatively, a conventional particle mixture may have a tendency to degrade over time (i.e., loss of function). 但是,与使用常规方法制备的制剂相比,本文中描述的纳米制剂可表现出相对长的保质期,而无样品降解(即保持功能)。 However, compared to the formulation prepared using conventional methods, nano-formulations described herein may exhibit a relatively long shelf life without degradation of the sample (i.e., hold function). 在一些实施方案中,根据本文中描述的系统和方法制备的纳米制剂的颗粒大小分布可通常是稳定的。 In some embodiments, the particle size of the nano-formulation was prepared according to the systems and methods described herein may generally be stable distribution. 即,对于通过聚焦声合适地形成的纳米制剂的小颗粒存在尽可能小的随时间合并成更大颗粒的趋势。 That is, for small nanoparticle formulation suitably formed by focused acoustic presence of the smallest possible over time merge into larger particles trends. 在一些实施方案中,在允许优选的纳米制剂静置12小时、24小时、2天、5天、1周、1 个月、1年或更长后,所述纳米制剂实施方案的平均颗粒大小和/或多分散指数波动不超过2%、5%或小于10%。 In some embodiments, allowed to stand in a preferred nanoformulation 12 hours, 24 hours, 2 days, 5 days, 1 week, 1 month, 1 year or more, an average particle size of the nano-formulation embodiments and / or polydispersity index fluctuations do not exceed 2%, 5%, or less than 10%. 在一些实施方案中,在纳米制剂中形成的颗粒的期望大小分布(例如,IOOnnul微米、10微米、50微米等,具有低F 1DI,等)可保持更长的时间,例如,1天至24 个月、2周至12个月或2个月至5个月。 In some embodiments, a desired nano-particles formed in the size distribution of the formulation (e.g., IOOnnul microns, 10 microns, 50 microns, etc., having a low F 1DI, etc.) can be maintained for a longer period of time, e.g., 1 day to 24 months, 2 weeks to 12 months, or 2 months to 5 months.

[0073] 如前所述,可在一些条件下向包含多种组合物的混合物施用聚焦声能,这导致形成多个具有约IOnm至约50微米平均大小的颗粒。 [0073] As described above, can be administered to the focused acoustic energy comprising a mixture of various compositions under some conditions, which leads to a plurality of about 50 micron average particle size to about IOnm. 在一些实施方案中,通过将所述混合物合适地暴露于聚焦声场一段时间而产生颗粒,其具有以下平均大小:约20nm至约lOOnm、约IOOnm至约10微米或约10微米至约50微米。 In some embodiments, by applying the mixture was suitably exposed to a focused acoustic field a period of time to produce particles having the average size: about 20nm to about lOOnm, about IOOnm to about 10 microns, or from about 10 microns to about 50 microns. 在一些情况下,在合适地暴露于聚焦声能后, 混合物中颗粒的平均大小可小于50微米、小于40微米、小于30微米、小于20微米、小于10 微米、小于1微米、小于500nm、小于lOOnm、小于50nm、小于20nm或小于10nm。 In some cases, after suitably exposed to the focused acoustic energy in the mixture the average particle size may be less than 50 microns, less than 40 microns, less than 30 microns, less than 20 microns, less than 10 microns, less than 1 micron, less than 500 nm, less than lOOnm, less than 50nm, less than 20nm or less than 10nm.

[0074] 根据本文中描述的方法,当暴露于聚焦声能时,混合物可发生颗粒大小的总体降低。 [0074] The methods described herein, when exposed to a focused acoustic energy, reduce the particle size of the overall mixture may occur. 在一些实施方案中,在合适的条件下声处理后,混合物中颗粒的平均大小可以降低至小于平均起始颗粒大小的50 %、20 %、10 %、1 %、0. 05 %的平均颗粒大小。 In some embodiments, the sonication under suitable conditions, the average size of the particles in the mixture may be reduced to less than 50% of the initial average particle size, 20%, 10%, 1%, 0.05% of the average particle size. 例如,在将混合物暴露于声能的聚焦区暴露合适的一段时间后,混合物中所有颗粒的平均大小为暴露于聚焦区之前平均起始颗粒大小的〇.〇1%至50%、0.05%至5%、0.1%至3%、0.5%至1%、1% 至10%、10%至20%、20%至30%、30%至40%或40%至50%。 For example, after exposure for a suitable period of time exposing the mixture to the focal zone of the acoustic energy, the average size of all particles in the mixture is exposed to 〇.〇1 to 50% before the average starting particle size of the focal zone, and to 0.05% 5%, from 0.1 to 3%, 0.5% to 1%, 1-10%, 10-20%, 20-30%, 30-40% or 40-50%. 在一个实施方案中,在使所述混合物经受小于60分钟的声处理后,混合物中多个颗粒的平均大小可以从至少200微米降低至小于1微米。 In one embodiment, in subjecting the mixture sonicated for less than 60 minutes, the average particle size of the mixture may be reduced from a plurality of at least 200 microns to less than 1 micron.

[0075] 在一些实施方案中,在暴露于聚焦区之前,混合物中平均起始颗粒大小可以是约10微米至约500微米、约50微米至约300微米或约100微米至约200微米。 [0075] In some embodiments, prior to exposure to the focal zone, the starting mixture the average particle size may be from about 10 microns to about 500 microns, about 50 microns to about 300 microns, or from about 100 microns to about 200 microns. 在一些情况下,在暴露于聚焦区之前,混合物中平均起始颗粒大小可大于10微米、大于50微米、大于100微米、大于200微米、大于300微米、大于500微米或大于1000微米。 In some cases, prior to exposure to the focal zone, the starting mixture the average particle size may be greater than 10 microns, greater than 50 microns, greater than 100 microns, greater than 200 microns, greater than 300 microns, greater than 500 microns or greater than 1000 microns.

[0076] 在一些实施方案中,经受聚焦声处理(这产生具有优选的颗粒大小范围的纳米制剂)的混合物不发生颗粒大小的总体降低。 The mixture [0076] In some embodiments, subjected to focused acoustic treatment (which produces particles of nanometer size range having a formulation preferred) reducing the particle size generally does not occur. 例如,聚焦声能可被用于处理具有多种组合物的混合物,其中混合物中的颗粒不是被处理而发生大小的降低,而是被声处理以形成特定类型的纳米制剂,例如脂质体/微团、纳米混悬剂和/或纳米乳剂。 For example, focused acoustic energy can be used to treat a variety of mixture composition, wherein the mixture of particles to be treated is not reduced as the size changes, but was sonicated to form a particular type of nano-formulations, such as liposomes / micelles, nano-suspensions and / or nanoemulsion. 在一些实施方案中,通过将合适组合物的混合物经受聚焦声能从而不发生平均颗粒大小降低而制备的纳米制剂可包封治疗剂。 In some embodiments, the focused acoustic energy from the average particle size does not decrease nanoformulation prepared encapsulated therapeutic agent can occur by subjecting a mixture of a suitable composition.

[0077] 如上讨论,聚焦声可被用于提高效率并给纳米制剂的制备带来很大程度的方便。 [0077] As discussed above, the sound can be focused to increase efficiency and to nanoformulations prepared great degree of convenience. 在一些实施方案中,用以产生合适纳米制剂的、混合物暴露于聚焦声场的时间较短。 In some embodiments, suitable for generating nanometer formulation, the mixture is exposed to focused acoustic field shorter time. 例如, 可将混合物暴露于聚焦声场小于2天、小于1天、小于12小时、小于10小时、小于5小时、 小于1小时、小于30分钟、小于10分钟或小于5分钟的时间以形成合适的纳米制剂。 For example, the mixture may be exposed to a focused acoustic field is less than 2 days, less than 1 day, less than 12 hours, less than 10 hours, less than 5 hours, less than 1 hour, less than 30 minutes, less than 10 minutes, or less than 5 minutes to form a suitable nanoformulation. 相反地,除使其他现有方法不可取的其他因素(例如,污染的可能性、样品的加热、低程度的可重复性,等)外,制备合适纳米制剂的现有方法可包括需要大量时间的多个步骤。 In contrast, among other factors (e.g., the possibility of contamination, the sample is heated, a low degree of repeatability, etc.) so that other desirable conventional method, the conventional method of preparation of suitable formulations may include nano requires much time the number of steps.

[0078] 聚焦声系统可在用于制备具有优选特性的纳米制剂的任何合适功率下运作。 [0078] focused acoustic system may operate at any power suitable for the preparation of nano-formulation having the preferred characteristics. 在一些实施方案中,聚焦声场在以下功率下运作:50瓦特至250瓦特、100瓦特至200瓦特、120 瓦特至170瓦特或约150瓦特。 In some embodiments, a focused acoustic field operating at the following power: 50 to 250 watts, 100-200 watts, 120-170 watts, or about 150 watts.

[0079] 在一些实施方案中,从起始混合物制备合适的纳米制剂所需要的时间、功率和/ 或精力的量很大程度上并不取决于混合物的体积。 [0079] In some embodiments, the time from the preparation of suitable starting mixture nanoformulation required, the amount of power and / or energy is not largely dependent on the volume of the mixture. 换句话说,对于扩大规模至具有更高体积(例如,250mL)的类似混合物,不必大幅延长小体积混合物(例如,5mL)所需的暴露于聚焦声能的时间。 In other words, for the scale up to a higher volume (e.g., 250 mL) in a similar mixture, need not extend significantly small volume of the mixture (e.g., 5 mL) to a desired exposure time focused acoustic energy. 例如,合适的纳米制剂可由合适地暴露于聚焦声场30分钟的各自具有5mL 和250mL体积的混合物产生。 For example, suitable formulations may be suitably nano exposed to a focused acoustic field for 30 minutes each with a mixture of 5mL and 250mL volume production. 在一些实施方案中,合适的纳米制剂可在混合物暴露于合适的聚焦声场后产生,混合物包含的体积为约ImL至约500mL、约5mL至约250mL或约IOmL至约IOOmL。 In some embodiments, suitable formulations may be exposed to the nano mixture after a suitable focused acoustic field is generated, the volume of the mixture comprises from about ImL to about 500 mL, about 5mL to about 250mL, or about IOmL about IOOmL.

[0080] 在一些情况下,与具有远远更小体积(少于IOmL)的混合物相比,将具有显著大体积(例如,多于5L)的混合物暴露于聚焦声能更长的时间以产生相似的纳米制剂结果,这可以是合适的。 [0080] In some cases, a mixture of much smaller volumes (less than IOmL) having compared to having significant large volume (e.g., greater than 5L) exposed to the mixture of focused acoustic energy to produce a longer time similar nanoformulation result, it may be appropriate. 例如使具有500mL体积的混合物经受聚焦声场60分钟,可产生纳米制剂,其具有与具有250ml体积的混合物经受聚焦声场30分钟的相似实例中的相似的特征。 For example a mixture having a volume of 500mL focused acoustic field is subjected to 60 minutes can produce nano-formulations, which have similar characteristics similar case focused acoustic field and subjecting the mixture having a volume of 250ml in 30 minutes. 因此, 在一些实施方案中,为获得特定的纳米制剂结果(例如,根据本文中描述的纳米制剂结果的平均颗粒大小、多分散指数、颗粒大小降低、颗粒大小分布,等),组合物的混合物可暴露于合适的聚焦声场,例如,每IOmL混合物30分钟、每50mL的混合物30分钟、每IOOmL的混合物30分钟、每250mL的混合物30分钟、每500mL的混合物30分钟或每1000 mL的混合物30分钟。 Thus, in some embodiments, to achieve a particular formulation results nanometers (e.g., according to the formulation results nano described herein, average particle size, polydispersity index, reducing the particle size, particle size distribution, etc.), a mixture of the composition may be exposed to a suitable focused acoustic field, e.g., every IOmL mixture for 30 minutes, each mixture 50mL for 30 minutes, each mixture IOOmL for 30 minutes, the mixture per 250mL of 30 minutes, 30 minutes or a mixture of 30 per 1000 mL of mixture per 500mL of minute. 相似地,在一些实施方案中,合适的纳米制剂结果可出现在组合物的混合物暴露于适当的聚焦声场之后,例如,每500微升的混合物15分钟、每ImL的混合物15分钟、每2mL 的混合物15分钟、每IOmL的混合物15分钟、每50mL的混合物15分钟或每IOOmL的混合物15分钟。 Similarly, in some embodiments, a suitable nanoformulations results can occur after the mixture composition is exposed to a suitable focused acoustic field, e.g., every 500 mixture microliter for 15 minutes, the mixture per ImL of 15 minutes and 2mL of mixture for 15 minutes, each mixture IOmL 15 minutes, the mixture every 15 minutes or every 50mL IOOmL mixture for 15 minutes.

[0081] 与体积方面的相似,对于一些实施方案,从起始混合物制备合适的纳米制剂所需要的时间、功率和/或精力的量可能并不很大程度上低取决于混合物的浓度。 [0081] similar volume aspect, for some embodiments, a suitable amount of time required nanoformulation prepared from a mixture of starting, power and / or energy may not be largely dependent on the low concentration of the mixture. 例如,具有相似颗粒大小分布的纳米制剂可通过使具有lmg/mL和100mg/mL各自浓度的组合物的混合物经受合适的聚焦声场30分钟而得到。 For example, a similar formulation with nano particle size distribution can be obtained by reacting a mixture having a lmg / mL and 100mg / mL of each concentration of the composition is subjected to a suitable focused acoustic field for 30 minutes. 在一些实施方案中,具有优选特征的纳米制剂可在合适的聚焦声场暴露于包含组合物的混合物之后出现,所述混合物具有约lmg/mL至约500mg/mL、约lmg/mL 至约100mg/mL、约1 SmT,至约100mg/mL 或约40mg/mL 至约70mg/mL 的浓度。 In some embodiments, the nano-formulation with preferred features may be exposed to a suitable focused acoustic field occurring subsequent to a mixture containing the composition, said mixture having from about lmg / mL to about 500mg / mL, from about lmg / mL to about 100mg / mL, about 1 SmT, to about 100mg / mL, or about 40mg / mL to a concentration of about 70mg / mL of. 例如,与在聚焦声处理之前的起始颗粒大小相比,在大幅变化的浓度(例如,lmg/mL 至10〇11^/1111^之间颗粒大小(例如,(190、(150、(110、平均大小等)的变化百分比差异可小于15%、小于10%、小于5 %、小于3 %或小于I %。 For example, compared to the starting particle size prior to focused acoustic treatment, particle size concentration changes greatly (e.g., lmg / mL to 10〇11 ^ / ^ between 1111 (e.g., (190, (150, (110 the percentage change in the difference, the average size and the like) may be less than 15%, less than 10%, less than 5%, less than 3%, or less than I%.

[0082] 在一些情况下,与具有远远更小浓度的特定组合物的混合物(小于lmg/mL)相比, 将具有显著大浓度的组合物的混合物(例如,大于5g/mL)暴露于聚焦声能更长的时间以产生相似的纳米制剂,这可以是有益的。 A mixture of a particular composition [0082] In some cases, having a much smaller concentration (less than lmg / mL) as compared to the composition of the mixture having significantly greater concentrations (e.g., greater than 5g / mL) is exposed to longer focused acoustic energy to produce similar nanoformulation, which may be beneficial. 例如使具有200mg/mL浓度的混合物经受聚焦声场60 分钟,可以产生纳米制剂,其具有与具有l〇〇mg/ml浓度的混合物经受聚焦声场30分钟的相似情况中的相似的特征。 For example a mixture having a 200mg / mL concentration focused acoustic field is subjected to 60 minutes can produce nano-formulation with similar characteristics similar to the case of a focused acoustic field and subjecting the mixture having l〇〇mg / ml concentration in 30 minutes. 在一些实施方案中,为实现特定的纳米制剂结果(例如,平均颗粒大小、多分散指数,等),可将组合物的混合物暴露于合适的聚焦声场,例如,每l〇〇mg/mL混合物30分钟、每200mg/mL混合物30分钟或每300mg/mL混合物30分钟。 In some embodiments, the formulation to achieve a particular result nanometers (e.g., average particle size, polydispersity index, etc.), a mixture of the composition may be exposed to a suitable focused acoustic field, e.g., every l〇〇mg / mL mixture 30 minutes per 200mg / mL of each mixture for 30 minutes or 300mg / mL mixture for 30 minutes.

[0083] 尽管可以领会上述相关参数(例如处理时间、混合物体积和组合物浓度)的任何组合可合适地用于生产具有优选的颗粒大小分布的纳米制剂,但下文中还是讨论了多个实例的颗粒大小分布。 [0083] appreciated that although the above-described parameters (e.g., processing time, volume of the mixture and concentration of the composition) in any combination can be suitably used to produce preferred formulations of nano particle size distribution, but are discussed below or multiple instances particle size distribution. 在一个实施方案中,在混合物暴露于聚焦声能之前,混合物中所有颗粒的至少90%可具有大于40微米的大小。 In one embodiment, before the mixture is exposed to focused acoustic energy in the mixture at least 90% of all particles may have a size greater than 40 microns. 但是,在混合物暴露于聚焦声能小于约5分钟或小于10分钟之后,混合物中所有颗粒的至少90%可具有小于40微米的所产生的大小。 However, after the mixture is exposed to focused acoustic energy of less than about 5 minutes or less than 10 minutes, the mixture at least 90% of all particles may have a size less than 40 microns produced. 在另一个实施方案中,在混合物暴露于聚焦声能之前,混合物中所有颗粒的至少90%可具有大于100微米的大小。 In another embodiment, the mixture is exposed to acoustic energy before focusing, the mixture at least 90% of all particles may have a size greater than 100 microns. 在混合物暴露于聚焦声能小于约10分钟后,混合物中所有颗粒的至少90%可具有小于20微米的所产生的大小。 After the mixture is exposed to focused acoustic energy of less than about 10 minutes, the mixture at least 90% of all particles may have a size of less than 20 microns produced. 在另一个实施方案中,在混合物暴露于聚焦声能之前,混合物中所有颗粒的至少90%可具有大于150微米的大小。 In another embodiment, the mixture is exposed to acoustic energy before focusing, the mixture at least 90% of all particles may have a size greater than 150 microns. 可是,在混合物暴露于聚焦声能小于约5分钟之后,混合物中所有颗粒的至少90%可具有小于15微米的大小。 However, after the mixture is exposed to focused acoustic energy of less than about 5 minutes, the mixture at least 90% of all particles may have a size less than 15 microns. 在另一个实施方案中,在混合物暴露于聚焦声能小于约10分钟之后,混合物中所有颗粒的至少90%可具有小于暴露于聚焦声能之前混合物中所有颗粒起始d90大小的20%。 In another embodiment, the mixture after exposure to the focused acoustic energy of less than about 10 minutes, the mixture at least 90% of all particles may be exposed to less than 20% of the mixture of all focused particle size d90 before starting acoustic energy. 在另一个实施方案中,在混合物暴露于聚焦声能小于约5分钟之后,混合物中所有颗粒的至少90 %可具有小于在混合物暴露于聚焦声能之前混合物中所有颗粒起始d90大小的10%。 After a further embodiment, the mixture is exposed to focused acoustic energy of less than about 5 minutes, the mixture at least 90% of all particles smaller than the exposure of the mixture may have focused acoustic energy to the mixture until 10% of all the starting d90 particle size .

[0084] 如上所述,混合物处理体积的提高可涉及声处理时间的延长。 [0084] As described above, increasing the volume of the mixture was treated may involve prolonged sonication time. 在一个实施方案中, 对于具有超过200mL (例如,约250mL)处理体积的混合物,混合物暴露于合适的聚焦声场小于约60分钟可导致混合物中所有颗粒的至少90%具有小于暴露于在聚焦声场暴露之前混合物中所有颗粒起始d90大小15%的大小。 In one embodiment, for having more than 200 mL (e.g., about 250 mL) treated volume of the mixture, the mixture is exposed to a suitable focused acoustic field of less than about 60 minutes can result in a mixture of at least 90% of all particles having less than the exposure to the exposure to the focused acoustic field before 15% of all the particles in the starting mixture size d90 size. 在另一个实施方案中,具有超过200mL处理体积的混合物暴露于聚焦声场小于约30分钟可导致混合物中所有颗粒的至少50%具有小于在向聚焦声场暴露之前混合物中所有颗粒起始d50大小20%的大小。 In another embodiment, having more than 200mL processing volume of the mixture is exposed to a focused acoustic field of less than about 30 minutes can result in a mixture of at least 50% of all particles having less than prior to exposure to the focused acoustic field of all particles in the starting d50 size mixture of 20% the size of. 在另一个实施方案中,将具有超过200mL处理体积的混合物暴露于聚焦声场小于约15分钟,可导致混合物中所有颗粒的至少10%具有小于在混合物暴露于聚焦声场之前混合物中所有颗粒起始dlO 大小15%的大小。 In another embodiment, the mixture having more than 200mL process volume is exposed to the focused acoustic field of less than about 15 minutes, can result in a mixture of at least 10% of all particles having before the sound field all particles in the starting dlO mixture was less than in the mixture is exposed to focused size 15% of the size. 在另一个实施方案中,具有超过200mL处理体积的混合物暴露于聚焦声场小于约60分钟导致混合物中所有颗粒的平均大小小于在混合物暴露于聚焦声场之前混合物中所有颗粒平均起始大小的〇. 5%。 In another embodiment, a mixture of more than 200mL process volume is exposed to the focused acoustic field of less than about 60 minutes resulted in a mean size of all particles in the mixture is less than in the mixture is exposed to focused square mixture the average starting size of all particles before the sound field. 5 %. 在另一个实施方案中,将具有超过200mL处理体积的混合物暴露于聚焦声场小于约10小时导致混合物中所有颗粒的平均大小小于在混合物暴露于聚焦声场之前混合物中所有颗粒平均起始大小的约〇. 2%。 In another embodiment, the mixture having more than 200mL process volume is exposed to the focused acoustic field of less than about 10 hours resulting in an average size of all particles in the mixture is less than the exposure of the focus mixture approximately square average starting size of all particles before the sound field in a mixture of . 2%.

[0085] 在本文中描述的多个实施方案、方面中考虑了包含具有约10至约400纳米直径颗粒群的纳米制剂,其中所述纳米制剂不被具有更大或更小直径(即,样品是单分散的)的颗粒污染。 [0085] The various embodiments described herein, aspects considered in the formulation comprises from about 10 nanometers to about 400 nm diameter particle group, wherein the nano-formulation does not have to be larger or smaller diameter (i.e., the sample monodisperse) of particulate contamination. 在一个实施方案中,颗粒包封化合物。 In one embodiment, compound particles encapsulated. 所述化合物可以是药物、营养品和药用化妆品。 The compound may be a drug, nutraceuticals and cosmeceuticals.

[0086] 在另一个实施方案中,本公开内容考虑用于形成纳米制剂的方法,其包括形成包含活性成分、液体分散介质和液体载体的混合物,其中化合物在所述介质中的大于3mg/mL。 [0086] In another embodiment, the present disclosure contemplates a method of forming a nano-formulations, comprising forming a mixture comprising the active ingredient, the liquid dispersion medium and a liquid carrier, wherein the compound is greater than 3mg / mL in the medium . 声能波列(wave train)朝向在容器中所容纳的混合物,以使混合物暴露于具有约100千赫至约100兆赫频率的声能场,且其聚集在主要位于容器中、宽度小于约2厘米的聚焦区。 Acoustic energy wave train (wave train) contained in the container toward the mixture so that the mixture is exposed to an acoustic field energy from about 100 kHz to about 100 MHz, and it is mainly gathered in the container, a width of less than about 2 cm focal region. 响应于暴露于聚焦区的声能,在混合物中形成了纳米制剂,其中纳米制剂包含混悬在液体载体中的液体分散介质的颗粒群。 In response to exposure to the acoustic focal zone can be formed in the mixture nanoformulation, wherein the formulation comprises nano-particles in the liquid carrier population suspended in a liquid dispersion medium. 每个颗粒至少含有一些活性成分,并且直径为约10纳米至约400纳米。 Each particle contains at least some of the active ingredient, and a diameter of about 10 nanometers to about 400 nanometers.

[0087] 在一个实施方案中,分散介质选自水性介质和油基介质。 [0087] In one embodiment, the aqueous medium and the dispersion medium is selected from oil-based media. 在一个实施方案中,油基介质选自但不限于:来自植物和海洋来源的饱和及不饱和油、硅油、矿物油和植物来源的油。 In one embodiment, the oil-based medium is selected from but not limited to: saturated and unsaturated oils, silicone oils, mineral oils, and oils derived from plants and plant-derived marine origin. 表面活性剂(如果包含的话)可以是任何离子性、非离子性或两性离子性材料。 Surfactant (if included) may be any ionic, nonionic or zwitterionic materials.

[0088] 在本发明的一个实施方案中考虑用于加强纳米晶体之合成的方法,所述纳米晶体由例如基于聚合物、基于金属或药物纳米颗粒形成(例如,金、铁氧化物和药物纳米晶体) 的过程产生。 [0088] contemplated for ways of strengthening of the as-synthesized nanocrystals In one embodiment of the invention, the nanocrystal by a polymer-based, metal based or drug nanoparticles formed e.g. e.g., gold, iron oxides and nano-drugs ( crystals) generating process.

[0089] 在另一个实施方案中,本公开内容的一些方面还可用于制备碳酸钙纳米颗粒,其可用于接合剂(cement)的制造过程,所述结合剂用作牙齿修复或其他牙科技术中的填料。 [0089] In another embodiment, some aspects of the present disclosure may also be used for the preparation of calcium carbonate nanoparticles, which can be used to manufacture cement (Cement), and the binding agent is used as a dental restoration or other dental techniques filler.

[0090] 在另一个实施方案中,本公开内容考虑均匀的聚焦超声声纳米制剂,其具有抗菌性。 [0090] In another embodiment, the present disclosure contemplates a uniform sound nanoformulation focused ultrasound, which have antibacterial properties. 在一个实施方案中,所述抗菌性包括声剪切力诱导的细胞裂解。 In one embodiment, the antimicrobial comprises an acoustic shear-induced cell lysis. 在一个实施方案中,所述纳米制剂是无菌的。 In one embodiment, the nano-formulation is sterile.

[0091] 根据本文中描述的一些方面,通过聚焦声制备的纳米制剂可包括反义化合物,其可被用作研究试剂、诊断助剂(diagnostic aid)、治疗剂和/或用于其他目的。 [0091] According to some aspects described herein, by focusing acoustic nanoformulation may comprise antisense compounds, which can be used as research reagents, diagnostic aids (diagnostic aid), therapeutic agent and / or for other purposes. 能够特异性抑制基因表达的反义寡核苷酸可用于阐明特定基因的功能,例如,SiRNA可用作作为筛选过程之一部分的转录的序列选择性抑制剂,所述筛选过程包括本领域技术人员所知的称为SELEX的技术。 Can specifically inhibit gene expression with antisense oligonucleotides can be used to elucidate the function of particular genes, for example, may be used as part of the screening process SiRNA sequence selective inhibitors of transcription, the screening process includes skilled in the art known technique called SELEX. 所述SELEX过程可允许鉴别具有独特序列的核酸分子,其中每个都具有与期望靶标化合物或分子特异性结合的性质。 The SELEX process may allow the identification of a nucleic acid molecule having a unique sequence, each having properties specifically binds to a desired target compound or molecule. 例如,反义化合物还可用于辨别生物学通路的多种成员的功能。 For example, antisense compound may also be used to identify the function of the various members of a biological pathway. 根据本文中描述的一些方面产生的纳米制剂还可包括其他低聚反义化合物,包括但不限于寡核苷酸模拟物。 Nanoformulations generated according to some aspects described herein may further comprise other oligomeric antisense compounds, including but not limited to oligonucleotide mimetics. 所述反义化合物可以是由聚焦声生产之纳米制剂中的活性组分,并具有约8个至约30个核苷酸碱基(即,约8个至约30个连接的碱基),但是本发明中也可使用更长和更短的序列。 The antisense compound may be produced nano-formulation of the active ingredient in the focused acoustic, and having from about 8 to about 30 nucleotide bases (i.e., from about 8 to about 30 linked bases), However, the present invention may also be used longer and shorter sequences. 例如,此类反义活性组分可以是反义寡核苷酸,例如包含约12个至约25个核苷酸的那些。 For example, such antisense active ingredient may be an antisense oligonucleotide, for example, those containing from about 12 to about 25 nucleotides.

[0092] 在一个实施方案中,本公开内容考虑生产纳米乳剂,其显著提高药物或其他活性化合物的效力。 [0092] In one embodiment, the present disclosure contemplates the production of nanoemulsions, which significantly improve the efficacy of the drug or other active compounds. 在一个举例说明性的方法中:a)鉴定对以治疗有效量施用之化合物不反应的对象;和b)在这样的条件下向所述对象递送纳米乳剂,从而使化合物的生物利用度被提高,并且其中所述化合物是治疗上有效的。 In an illustrative method: Object a) identification of a compound is administered in a therapeutically effective amount of non-reactive; and b) delivering to the subject a nanoemulsion under such conditions, so that the bioavailability of the compounds is increased and wherein said compound is therapeutically effective. 在一个实施方案中,所述提高的生物利用度包括选自降低的Tmax、升高的Cmax和升高的AUC的药物代谢动力学参数。 In one embodiment, to improve the bioavailability includes reducing the Tmax of selected, drug metabolism increased Cmax and AUC increased kinetic parameters. 在一个实施方案中, 所述递送包括选自以下的方法:递送纳米乳剂的经口、经皮、静脉内、腹膜内、肌内和皮下方法。 In one embodiment, the method comprises delivering selected from: nanoemulsion oral delivery, transdermal, intravenous, intraperitoneal, intramuscular and subcutaneous methods.

[0093] 纳米乳剂可通过不同类型的方法形成,例如高能乳化法和低能相转变温度法。 [0093] The nano-emulsion may be formed by various types of methods, such as high energy emulsification method and a phase transition temperature of the low-energy method. 在高能乳剂形成法中,使用微流化设备使纳米乳剂组分(例如,油、水、表面活性剂和任选的药物、营养品或药用化妆品试剂)的混合物经受在高压下(例如,至少24, OOOpsi)的连续紊流(turbulent flow)以形成纳米乳剂(例如,如Cook等在1984年2月21日提交的美国专利4, 533, 254和5月26日提交的美国专利4, 908, 154中所描述的那样)。 In high energy emulsion formation method, a microfluidization apparatus causes nanoemulsion components (e.g., oil, water, surfactant and optional pharmaceutical, nutraceutical or cosmeceutical agent) was subjected to high pressure (e.g., at least 24, OOOpsi) continuous turbulent flow (turbulent flow) to form a nanoemulsion (e.g., as in U.S. Patent Cook et al February 21, 1984, filed 4, 533, 254 and U.S. Patent No., filed 26 May 4, 908, as) 154 as described.

[0094] 或者,纳米乳剂可通过低能"自组装纳米乳剂"(self-assembly nanoemulsion, SANE)方法形成,而没有通过将能够温度依赖性相转变(例如,非离子性聚乙氧基化表面活性剂)的表面活性剂与其他纳米乳剂组分(例如,油、水和任选的药物、营养品或药用化妆品试剂)相组合的微流化装置(microfluidizer)处理。 [0094] Alternatively, the nanoemulsion may be via a low energy "self-assembly nanoemulsion" (self-assembly nanoemulsion, SANE) forming method, without passing through the temperature dependence of the phase transition will be able to (e.g., polyethoxylated nonionic surfactants microfluidization device agent) surfactant nanoemulsion with other components (e.g., oil, water and optionally a pharmaceutical, nutraceutical or cosmeceutical agent) in combination (Microfluidizer) process. 该技术在公布的PCT申请号W0/2009/121069中被引用。 In PCT Application No. W0 / 2009/121069 was published in the technical reference. 所述纳米乳剂组分被混合并加热至超过表面活性剂的相变温度(phase inversion temperature,PIT)(即,表面活性剂对不同相的亲合力改变的温度)。 The nanoemulsion components are mixed and heated to the phase transition temperature (phase inversion temperature, PIT) (i.e., surfactants of different phases affinity force change temperature) exceeds a surfactant. 例如,水包油型(0/W)粗乳剂(macroemulsion)超过PIT时可发生可逆的温度依赖的过渡相转变,以形成油包水型(W/0)乳剂。 For example, oil-in-water (0 / W) emulsion of crude (macroemulsions) reversible temperature-dependent transition may occur when the phase shift exceeds PIT to form a water-in-oil (W / 0) emulsion. 随后的低于PIT (例如通过热冷却或添加水)的W/0 乳剂的迅速冷却可导致形成悬浮于水中之油滴的动力学上稳定的0/W纳米乳剂组合物(任选地含有药物、营养品或药用化妆品试剂)。 Subsequent below the PIT (e.g. by heat or adding cooling water) W / 0 emulsion is rapidly cooled may result in the formation of a stable suspension of oil droplets in the water of the kinetics of 0 / W nanoemulsion composition (optionally containing pharmaceutical , nutraceutical or cosmeceutical agent). 可进行热冷却以形成纳米乳剂,例如,通过将包含W/0乳剂的容器放置于冰浴中。 Heat may be cooled to form a nanoemulsion, for example, by emulsion comprising a container is placed W 0 / in an ice bath. 除非另有指明,否则"迅速冷却"指以适于形成无微流化之纳米乳剂的速率进行冷却。 Unless otherwise indicated, "rapidly cooled" refers to a suitable rate of formation of the non-microfluidized nanoemulsion cooled.

[0095] 但是,这些处理的每一种都具有显著的技术和商业缺点。 [0095] However, each of these processes have significant technical and commercial disadvantages. 在微流化的情况下,混合物在处理期间经受极高的压力(例如,40, OOOpsi),这可对活性成分具有不利的作用。 In the case of the microfluidized mixture is subjected to extremely high pressures (e.g., 40, OOOpsi) during processing, which may have an adverse effect on the active ingredient. 此外,作用于流体的这些高压强和高剪切应力可生热,这使活性组分进一步降解。 In addition, the role of these high pressures and high fluid shear stress may be heat, which further degradation of the active ingredient. 微流化设备需要敏感和复杂的操作以及操作者相当程度的技术。 Operation, and a considerable degree of skill of an operator sensitive and complex devices require microfluidic. 此外,处理后微流化装置在系统中留下很大一部分不可回收的材料,因此损失了宝贵的产率。 In addition, the post-processing apparatus microfluidization leaving a large part of the material can not be recovered in the system, and therefore the loss of valuable yield. 该产率损失对于50mL以下体积的处理来说尤其显著,在处理期间经常损失材料的20%至40%。 The yield loss for the volume of 50mL processing is especially significant, often 20 to 40% loss of material during handling. 此外,微流化设备在样品之间需要清洗,因此具有样品间交叉污染的可能性。 Further, microfluidization device to be cleaned between samples, thus having the possibility of cross-contamination between samples.

[0096] 在SANE技术的情况下,必须使用特定的表面活性剂和比例。 [0096] In the case of technique SANE, you must use a specific proportion and a surfactant. 虽然可以达到很小的微滴大小和紧密的大小分布,但是用SANE技术产生的纳米乳剂表现出缩短的保质期和降低的随时间的稳定性,尤其是当经受阳光和温度时。 Although it is possible to achieve a small droplet size and tight size distribution, but produced by techniques SANE nanoemulsion exhibits a shortened shelf-life stability and reduced over time, especially when subjected to sunlight and temperature. 简单地在室温下贮存SANE样品在一些情况下经数周可引起降解。 SANE simply stored samples at room temperature can cause degradation of several weeks in some cases. 此外,使用SANE技术必须使用非常特定的表面活性剂、比例和组合以获得稳定的纳米乳剂。 Furthermore, the use SANE technology must use very specific surfactants, and combinations of proportions to obtain stable nanoemulsion. 对于制剂的药物代谢动力学性能来说,这些表面活性剂可以是有害于的。 For kinetic pharmacokinetic properties of the formulation, these surfactants can be detrimental to the. 此外,表面活性剂在其他方面可以是有害的,例如毒性或缩短保质期。 Further, the surfactant can be harmful in other ways, such as toxic or shortened shelf life. 与其他技术相比,已知SANE技术用于包封较小量的包封物(encapsulant)(例如,依赖于油与表面活性剂的比例(I :5),SANE处理可容纳1~2mg/mL,但是微流化系统可超过4mg/mL)。 Compared with other techniques, encapsulation techniques known SANE (encapsulant) (e.g., dependent on the oil to surfactant ratio (I for encapsulating a small amount: 5), SANE process can accommodate 1 ~ 2mg / mL, but the microfluidic system may exceed 4mg / mL). [0097] 虽然对于形成纳米乳剂的一些现有技术可具有缺点,使用根据本发明一些方面的聚焦声的可以是对微流化、SANE和基于聚合物之技术的补充。 [0097] While some prior art for forming nanoemulsions may have disadvantages, the use of focused acoustic accordance with some aspects of the present invention may be a microfluidization, the SANE and supplement of the polymer-based techniques. 在SANE处理的情况下,可在处理的预热和相转变温度步骤期间应用聚焦声处理,可能产生更令人满意的大小分布、更低或更宽范围的表面活性剂要求。 In the case of SANE treatment can be applied during the preheating phase transition temperature and a focused acoustic processing step, it may produce a more desirable size distribution, a surfactant requires less or more broadly. 聚焦声还可与微流化相组合,在流化装置(fluidizer) 通道的上游或者下游,或者还在通道本身中,因此提高能量水平并产生更好的大小分布、或提高生产能力或降低压力要求。 Focused acoustic microfluidization can also be combined with, the upstream or downstream flow apparatus (FLUIDIZER) channel, the channel itself, or also, thereby increasing energy levels and produce better size distribution, or to improve the production capacity or reduce pressure Claim. 实施例 Example

[0098] 以下实施例旨在举例说明本发明的某些实施方案,但不被解释为限制并且不例示本发明的全部范围。 [0098] The following examples are intended to illustrate certain embodiments of the invention, but are not to be construed as limiting and do not exemplify the full scope of the invention.

[0099] 实施例1 [0099] Example 1

[0100] 对于布洛芬(来自Spectrum Chemicals)、桂利嚷(来自Spectrum Chemicals)、口引哚美辛(来自Spectrum Chemicals)和灰黄霉素(来自MP Bio),制备在水(通过Barnstead 水纯化系统去离子化并纯化)、甲基纤维素(来自Sigma Aldrich)和月桂基硫酸钠(来自Fisher Scientific)中的混悬剂混合物。 [0100] and for ibuprofen (from Spectrum Chemicals), cinnarizine cried (from Spectrum Chemicals), indomethacin lead port (from Spectrum Chemicals), and griseofulvin (from MP Bio), prepared in water (Barnstead water by deionized purification system and purified), a suspension mixture of methyl cellulose (from Sigma Aldrich) and sodium lauryl sulfate (from Fisher Scientific) in. 这些混悬剂混合物的起始颗粒大小经受聚焦声处理而降低,所述聚焦声处理在150瓦特功率下使用Covaris SF220高性能制剂处理系统。 These suspensions particle size of the starting mixture is subjected to focused acoustic treatment to reduce the use of focused acoustic treatment formulation Covaris SF220 high-performance processing system at 150 watts power. 颗粒大小分布用Malvern Zetasizer Nano ZS-90在纳米颗粒大小范围测量,并且用Malvern Mastersizer2000在微米颗粒大小范围测量。 Particle size distribution with a size range ZS-90 measured in the Malvern Zetasizer Nano nanoparticles and micron particle size range measured using Malvern Mastersizer2000.

[0101] 颗粒大小的降4氏:15mg/mL·的布洛芬、桂禾丨|嗪、口引P朵美辛矛口灰黄霉素 [0101] 4 & apos particle size reduction: 15mg / mL · ibuprofen, Gui Wo Shu | triazine, lead port P duo indomethacin lance port griseofulvin

[0102] 对于2mL、12mL和18mL批次的15mg/mL的布洛芬、桂利嗪、Π 引哚美辛和灰黄霉素, 混悬剂混合物包含水、0. 5%甲基纤维素和0. 1 %的月桂基硫酸钠。 [0102] For 2mL, 12mL and 18mL batches of 15mg / mL ibuprofen, Cinnarizine, [pi primer indomethacin and griseofulvin, suspensions mixture comprising water, 0.5% methyl cellulose and 0.1% of sodium lauryl sulfate. 使所述2mL、12mL和18mL 批次分别经受5分钟、5分钟和10分钟的聚焦声处理。 Said 2mL, 12mL and 18mL batches were subjected to 5 minutes, 5 minutes and 10 minutes focused acoustic treatment. 图6不出聚焦声处理前后的被处理的15mg/mL浓度布洛芬在50 X放大下的显微照片(具有50微米比例尺)。 To be treated before and after the process of FIG. 6 not focused acoustic 15mg / mL X-50 at a concentration of Ibuprofen magnification photomicrograph (having a 50 micrometers scale). 与被聚焦声处理颗粒之后图像402所示的相应颗粒相比,在暴露于聚焦声之前的图像400描述的颗粒远远更大(例如,15~20X)。 Compared with the corresponding particles are shown after the focused acoustic treatment 402 particle images, particles described image 400 prior to exposure to focused acoustic far greater (e.g., 15 ~ 20X). 表1中提供了四种化合物中每一种的颗粒大小的结果(除非另外指明,颗粒大小按d90记录)。 Table 1 provides the results of each of the four compounds of particle size (unless otherwise specified, the particle size d90 by the recording).

[0103] 表1 :布洛芬、桂利嗪、吲哚美辛和灰黄霉素的颗粒大小结果(d90)。 [0103] Table 1: Ibuprofen, Cinnarizine, indomethacin and griseofulvin results of particle size (d90).

[0104] [0104]

Figure CN103124592BD00181

[0105] 颗短大小的降ί氐:lmR/mL、15mR/mL矛口IOOmRZmL的布洛芬 [0105] particle size of the short drop ί Di: lmR / mL, 15mR mL lance port IOOmRZmL ibuprofen /

[0106] 然后改变2mL、12mL和18mL固定体积的各个混悬剂中布洛芬的浓度。 [0106] and then change the various suspensions 2mL, 12mL and 18mL fixed volume concentration of ibuprofen. 表2列出每种浓度下布洛芬的d90颗粒大小。 Table 2 lists the d90 particle size of the ibuprofen at each concentration. 如示,即使混悬剂浓度大幅改变,所述d90颗粒大小结果也不显著改变。 As shown, a substantial change even if the concentration of suspension, the particle size d90 result is not significantly changed. 例如,聚焦声处理10分钟后,在浓度(即,lmg/mL、15mg/mL和100mg/mL)之间d90颗粒大小的最大变化(即,39. 53-34. 04 = 5. 49)与起始d90颗粒大小(即,203. 67) 相比的百分差异小于3%。 For example, focused acoustic treatment for 10 minutes, between the concentration (i.e., lmg / mL, 15mg / mL and 100mg / mL) maximum change d90 particle size (i.e., 39 53-34 04 = 5.49) and starting d90 particle size (i.e., 203.67) percent difference compared to less than 3%. 因此,于此证明为制备具有浓度大幅变化的纳米制剂的聚焦声学处理可产生基本上相似的结果。 Thus, this process proves to be prepared having an acoustic focus nanoformulations concentration largely changes may produce substantially similar results.

[0107] 表2 :lmg/mL、15mg/mL和100mg/mL布洛芬的颗粒大小结果(d90)。 [0107] Table 2: lmg / mL, 15mg / mL and 100mg / mL ibuprofen result particle size (d90).

[0108] [0108]

Figure CN103124592BD00191

[0109] 颗粒大小的降低:纳米-混悬剂 [0109] reduce the particle size: Nano - suspensions

[0110] 对于2mL批次的5mg/mL的布洛芬、桂利嗪、π引哚美辛和灰黄霉素,混悬剂混合物包括水、0. 025%的甲基纤维素和0. 1%的月桂基硫酸钠。 [0110] For batches 2mL 5mg / mL ibuprofen, Cinnarizine, [pi] indole indomethacin and griseofulvin, suspensions mixture comprising water, 0.025% methylcellulose and 0. 1% sodium lauryl sulfate. 每个批次分别经受15分钟和30分钟的聚焦声处理。 Focusing each batch sonicated for 15 min and 30 min respectively subjected. 表3列出四种化合物每种的平均颗粒大小结果。 Table 3 shows the results of an average particle size of each of the four compounds. 在15分钟内,产生了对于每种混合物具有IOOnm至280nm的平均颗粒大小的纳米混悬剂。 Within 15 minutes, each mixture to produce the nano-particles having an average size of 280nm to IOOnm suspension. 在30分钟内,获得20nm 至97nm的平均颗粒大小范围。 Over 30 minutes, to obtain an average particle size range of 20nm to 97nm.

[0111] 表3 :纳米-混悬剂的平均颗粒大小结果。 [0111] Table 3: Nano - an average particle size of the result suspensions.

[0112] [0112]

Figure CN103124592BD00192

[0113] 颗粒大小降低:规樽扩大至250mL的布洛芬 [0113] particle size reduction: regulatory expanded to 250mL bottles of ibuprofen

[0114] 使用规模扩大系统并且不改变颗粒大小降低处理的机械属性,将布洛芬混悬剂混合物提高至250mL。 [0114] A scale system and without changing the particle size reduction of the mechanical properties of the process, the ibuprofen suspension mixture was increased to 250mL. 流速设为30mL/分钟。 Set flow rate 30mL / min. 系统的同质性和稳定性通过从250mL混悬剂的不同深度(例如,顶部、中部和底部深度)取样来显示。 Homogeneity and stability of the system is shown by the different depths (e.g., top, middle and bottom depths) 250 mL of the suspension sample. 使用稳定性指示方法作为指导通过HPLC来分析混悬剂的等分量。 Stability-indicating method using as a guide suspensions aliquots analyzed by HPLC. 在首个15分钟测量时间点,混悬剂显示出同质性,其中混悬剂的颗粒大小分布具有〇. 40%的相对标准偏差。 In the first 15 minutes measurement time point, suspensions exhibit homogeneity, wherein the suspension has a particle size distribution of the square. The relative standard deviation of 40%. 经过60分钟的聚焦声处理,混悬剂的颗粒大小分布被测量具有0. 38%的相对标准偏差。 After 60 minutes of focused acoustic, suspension particle size distribution is measured with 0.38% relative standard deviation. 此外,布洛芬显示出化学稳定性,60分钟的处理中不出现杂质增长。 In addition, ibuprofen exhibit chemical stability, increase the impurity does not occur in 60 minutes. 表4示出所述规模扩大处理的颗粒大小结果。 Table 4 shows the particle size scale processing results. 图7举例说明了对于d90颗粒大小410、d50颗粒大小412和dlO颗粒大小414随时间的此类大小降低的结果。 Figure 7 illustrates the results of particle size d90 410, d50 particle size of 412 and 414 dlO particle size reduced with respect to time of such magnitude.

[0115] 表4 :对于规模扩大至250mL的布洛芬颗粒大小结果(d90、d50、dlO)。 [0115] Table 4: Ibuprofen respect to the scale of particle size results 250mL (d90, d50, dlO).

[0116] [0116]

Figure CN103124592BD00201

[0117] 颗粒大小降低:规樽扩大至250mL的样利嗪 [0117] The particle size reduction: Regulation sample bottles expanded to 250mL Cinnarizine

[0118] 以与规模扩大之布洛芬混悬剂类似的方式将桂利嗪混悬剂混合物提高至250mL。 [01] in order to expand the scale and the suspension of ibuprofen similar manner Cinnarizine suspension mixture increased to 250mL. 所述混悬剂混合物包含水、0. 025%甲基纤维素和0. 1 %月桂基硫酸钠,远低于临界胶束浓度范围。 The suspension mixture comprising water, 0.025% methylcellulose and 0.1% sodium lauryl sulfate, well below the critical micelle concentration range. 图8举例说明了根据对桂利嗪混悬剂随时间之曲线420的颗粒大小降低的图。 FIG 8 illustrates a graph of particle size reduction cinnarizine suspensions 420 over time in accordance with FIG. 起始平均颗粒大小是约200微米。 Starting mean particle size of about 200 microns. 对250mL混悬剂进行1小时的处理之后,达到了1微米的平均颗粒大小。 After 250mL suspension for 1 hour treatment, to achieve an average particle size of 1 micron. 通过约9小时的时间,平均颗粒大小稳定在约200nm。 By about 9 hours, the average particle size stable at about 200nm.

[0119] 实施例2 [0119] Example 2

[0120] 图9描述了根据随时间之曲线430、432、434的颗粒大小降低的图。 [0120] FIG. 9 depicts a graph of particle size reduction over time 430,432,434 FIG. 曲线430涉及材料D15,曲线432涉及材料Z27,且曲线434涉及材料K19。 Curve 430 relates to material D15, curve 432 relates to a material Z27, and curve 434 relates to a material K19.

[0121] 实施例3 [0121] Example 3

[0122] 使在无表面活性剂的水中规模扩大的250mL槲皮素样品经受聚焦声场。 [0122] subjecting the focused acoustic field of quercetin sample size 250mL water surfactant-free enlarged. 图10举例说明了沿着曲线440的颗粒大小降低的图,表现出在80分钟内平均颗粒大小从大于200 微米降低至小于10微米。 Figure 10 illustrates the particle size reduction along the curve 440 of FIG, showed an average particle size to less than 200 microns from greater than 10 microns in 80 minutes. 在聚焦声处理期间,样品的温度控制在24°C。 During the focused acoustic treatment, the sample temperature is controlled at 24 ° C.

[0123] 实施例4 [0123] Example 4

[0124] 使水中吲哚美辛的混合物经受聚焦声处理。 [0124] indol-mixture so that the water is subjected to a focused acoustic indomethacin treatment. 根据图11的分布曲线450,暴露于聚焦声能之前的平均颗粒大小为100至200微米。 The profile 450 of FIG. 11, the average particle size prior to exposure to the focused acoustic energy is from 100 to 200 microns. 图12描述了在混合物暴露于聚焦声能之后的分布曲线452,示出平均颗粒大小为约5微米。 Figure 12 depicts the profile of the mixture after exposure to the focused acoustic energy 452, shown average particle size of about 5 microns.

[0125] 实施例5 [0125] Example 5

[0126] 将Solutol HS15(非离子性增溶剂)与油和水相混合,以产生空白纳米乳剂(nanoemulsion blank)。 [0126] The Solutol HS15 (nonionic solubilizer) with the oil and aqueous phase, to generate a blank nanoemulsion (nanoemulsion blank). 对250mL的体积进行处理以显示可扩展性。 250mL volumetric processed to show scalability.

[0127] 图13举例说明纳米乳剂的三种不同分布460a、462a、464a,表现出显著的多分散性。 [0127] Figure 13 illustrates different distributions 460a, 462a, 464a of the three types of nano emulsion, showed significant polydispersity. 然后将混合物加热至50°C并经受5分钟160瓦特的聚焦声处理。 The mixture was then heated to 50 ° C and subjected to 5 minutes of 160 watts focused acoustic treatment.

[0128] 图14示出由聚焦声处理所产生的颗粒大小分布460b、462b、464b。 [0128] FIG. 14 shows the particle size generated by the focused acoustic processing profile 460b, 462b, 464b. 观察到每种纳米乳剂是单分散的,具有20. 27nm的平均颗粒大小。 Each observed monodisperse nanoemulsions, having a mean particle size of 20. 27nm.

[0129] 图15描述了经受24小时静置之后纳米乳剂的颗粒大小分布460c、462c、464c。 [0129] FIG. 15 depicts nanoemulsion was allowed to stand 24 hours after subjected to particle size distribution 460c, 462c, 464c. 观察到颗粒保持稳定,具有19. 62nm的平均颗粒大小。 Observed to remain stable particles having a mean particle size of 19. 62nm.

[0130] 实施例6 [0130] Example 6

[0131] 基于聚焦声的脂质体形成已被证明在一定的大小以下不降解生物材料。 [0131] Based focused acoustic forming liposomes have been proven not biodegradable material a certain size or less. 将2mg Phospholipon_90G (Lipoid LLC)与130 微升去离子水组合,将10 ~30mgPhospholipon_90G 以10mg/mL与2mL去离子水组合。 The 2mg Phospholipon_90G (Lipoid LLC) and 130 microliters of deionized water combination, to 10 ~ 30mgPhospholipon_90G at 10mg / mL in combination with 2mL of deionized water. 分别以18瓦特(150PIP,10%工作周期,200个周期/猝发(burst))和150瓦特(300PIP,50%工作周期,1000个周期/猝发)向混合物施用聚焦声场30秒,同时使混合物保持在4°C的恒定温度下。 Respectively, 18 watts (150PIP, 10% duty cycle, 200 cycles / burst (Burst)) and 150 watts (300PIP, 50% duty cycle, 1000 cycles / burst) is administered to a mixture of a focused acoustic field for 30 seconds while the mixture was kept at a constant temperature at 4 ° C.

[0132] 图16描述了纳米制剂的颗粒大小分布470。 [0132] Figure 16 depicts the particle size distribution of 470 nano-formulation. 形成了具有小于IOOnm平均颗粒大小的包封DNA的单分散脂质体群。 Forming a monodisperse population of liposomes having an average particle size of less than IOOnm encapsulated DNA. 为评价稳定性,使所述纳米制剂在实验室条件下静置1周, 然后再次测试颗粒大小。 To evaluate the stability of the nano-formulation was allowed to stand under laboratory conditions for 1 week, then tested for particle size again.

[0133] 图17示出了1周时间之后纳米制剂的颗粒大小分布472。 Nanoformulations after [0133] FIG. 17 shows the particle size distribution for 1 week 472. 平均颗粒大小仍然小于100nm。 The average particle size is still smaller than 100nm.

[0134] 测试以上处理条件以确定对DNA大小的影响。 [0134] The above test process conditions to determine the effect on DNA size. IOObp的DNA链可用作起始材料,并经受与脂质体形成所要求的那些相一致的聚焦声处理水 IOObp DNA strand used as a starting material and subjected to a focused acoustic coincides those formed liposomes required treated water

[0135] 平。 [0135] level. 在聚焦声的用量下,所述IOObp DNA材料不示出降解的迹象,并保持全部完整。 The amount of focused acoustic at the IOObp DNA material not shown signs of degradation, and holding all complete. 该实施例示出,使用聚焦声处理条件,具有约IOObp或更长(或更短)长度的多核苷酸链未被破坏,并被包封。 This embodiment illustrates, using focused acoustic processing conditions, having about IOObp or longer (or shorter) length of the polynucleotide strand is not damaged, and encapsulation. 该实施例还证明了能够产生包含siRNA或其他多核苷酸颗粒(直径或其他大小为约10纳米至约400纳米)的纳米制剂,而不使多核苷酸显著地降解。 This example also demonstrates the ability to produce nano-formulation comprising a polynucleotide siRNA or other particles (diameter or other size of about 10 nm to about 400 nm), without causing significant degradation of the polynucleotide.

[0136] 实施例7 [0136] Example 7

[0137] 将合适的油和表面活性剂与生物活性成分(活性成分)和DI水一起相混合。 [0137] Suitable oils and the surfactant with the biologically active component (active ingredient) and DI water are mixed together. 然后使混合物经受由Covaris,Inc. of Woburn, MA所售声处理设备产生的高强度(10% )聚焦声能,工作周期为20~50次,且周期/猝发为约200次。 The mixture is then subjected to a Covaris, Inc. High strength (10%) of Woburn, MA sold sound processing apparatus generates the focused acoustic energy, the duty cycle is 20 to 50 times, and cycles / burst is about 200 times. 发现该处理产生具有约10~ 400nm大小的油颗粒的纳米乳剂,其中每个油颗粒包含生物活性成分,并悬浮在DI水载体中。 The process was found to produce a nanoemulsion having a size of about 10 ~ 400nm oil particles, wherein each particle comprises a biologically active oil component and suspended in DI water carrier. 由AFA的某些条件产生的一些制剂以及大豆油与Tween-80的组合表示于表7~12中, 以示出AFA技术对乳剂的影响。 Some formulations and soybean oil produced by certain conditions of AFA in combination with Tween-80 shown in Table 7 to 12, to show the influence on the emulsion technique AFA. 非常低浓度的Tween-80和油(例如表7中所示)在生产具有与AFA能量暴露时间无关之期望性质的纳米乳剂中是不成功的。 Very low concentrations of nanoemulsion Tween-80 and oils (e.g., shown in Table 7) having the desired properties regardless of the exposure time and energy in the production AFA is unsuccessful. 表8示出在10分钟的暴露条件下AFA能量的作用。 Table 8 shows the effect of energy AFA at 10 minutes of exposure conditions. 表9示出在暴露于AFA能量5和10分钟的条件下对起始混合物之制剂的作用。 Table 9 shows the effect on the formulation of the starting mixture under conditions of exposure to the energy AFA 5 and 10 minutes. 在表10中,示出暴露于AFA能量5和10分钟对制剂的巨大作用。 In Table 10, it shows the great effect of exposure to 5 and 10 minutes for formulation AFA energy. 表11示出在15、30、40和60分钟的运行时间下进一步分析和开发纳米乳剂的希望,这是因为混合物制剂和声能条件产生的包括相当窄颗粒大小范围(例如,包括几乎87%的颗粒)的纳米乳剂具有260nm的大小。 Table 11 hope for further analysis and development of nanoemulsion at 15, 30 and 60 minutes run time is shown, this is because a relatively narrow particle size range comprises a mixture of formulation conditions and acoustic energy produced (e.g., including almost 87% particles) having a nanoemulsion of size 260nm. 在15分钟暴露时,产生了组合的最大作用。 At 15 minute exposure, it produced the largest effect of the combination.

[0138] 表6. [0138] Table 6.

[0139] [0139]

Figure CN103124592BD00211

[0140] [0140]

Figure CN103124592BD00221

[0141] 表7· 0· 25 克大豆油+0· 25 克Tween80+19. 5ml DI 水。 [0141] Table 7 · 0 · 0 + 25 g soybean oil 25 g · Tween80 + 19. 5ml DI water.

[0142] [0142]

Figure CN103124592BD00222

Figure CN103124592BD00231

[0143] 表8· 0· 5 克大豆油+0· 5 克Tween80+19ml DI 水。 [0143] Table 8 · 0 · 5 g of soybean oil + 0 · 5 g Tween80 + 19ml DI water.

[0144] [0144]

Figure CN103124592BD00232

[0145] 表9. 1 克大豆油+1 克Tween80+18ml DI 水。 [0145] Table 9.1 grams soybean oil + 1 g Tween80 + 18ml DI water.

[0146] [0146]

Figure CN103124592BD00241

[0147] 表10. 1 克大豆油+2 克Tween80+17ml DI 水。 [0147] Table 10.1 grams of soybean oil + 2 g Tween80 + 17ml DI water. [0148] [0148]

Figure CN103124592BD00242

[0150] 表11. 1 克大豆油+2 克Tween80+17ml DI 水。 [0150] Table 11.1 grams of soybean oil + 2 g Tween80 + 17ml DI water.

[0149] [0149]

[0151] [0151]

Figure CN103124592BD00251

[0152] 表12. 1 克大豆油+2 克Tween80+17ml DI 水,10%强度。 [0152] Table 12.1 grams of soybean oil + 2 g Tween80 + 17ml DI water, 10% strength.

[0153] [0153]

Figure CN103124592BD00252

[0154] 实施例8 [0154] Example 8

[0155] 用起始包含1份DMA、99份PVP/SDS稳定剂和非洛地平的2mL样品形成晶体纳米颗粒。 [0155] Including 1 starting with DMA, 99 parts of PVP / SDS stabilizer and 2mL sample felodipine crystalline nanoparticles formed. 用Covaris S220机处理样品,使用18°C的水浴温度、50%工作周期、75瓦特峰入射功率(peak incident power, PIP)、1000周期/粹发和20分钟的总处理时间。 Treatment of the sample with a machine Covaris S220, using a water bath temperature of 18 ° C, 50% duty cycle, 75 watts incident power peak (peak incident power, PIP), 1000 cycles / pure fat and total processing time of 20 minutes. 该处理导致晶体纳米颗粒的形成(生长),其中100%的颗粒具有约153. 2nm的平均大小,最小大小为约137. 5nm并且最大大小为约168. 7nm。 This process results in the formation of crystalline nanoparticles (growth), where 100% of the particles have an average size of about 153. 2nm, the minimum size of about 137. 5nm and a maximum size of about 168. 7nm. 因此,在相对短的时间阶段内产生了非常窄或紧密的大小范围的颗粒。 Thus, a very tight or narrow size range particles in a relatively short period of time.

[0156] 要理解的是,本发明的应用不受对以下描述中列出或附图中图示之组分的详细解释和排列所限制。 [0156] is to be understood that the present invention is applied and a detailed explanation is not listed or arrangement of components illustrated in the drawings in the following description is limited. 实施本发明的其他实施方案和方式是可能的。 Other embodiments and embodiments of the invention are possible. 本文中使用的措辞和术语用于描述的目的,并且不应被认为是限制。 Phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. "包括"、"包含"或"具有"及其变化形式的使用意味着包括其后所列出的项目及其等价形式以及额外的项目。 "Including", "containing" or "having" and variations thereof is meant to encompass the items listed thereafter and equivalents thereof as well as additional items. 因此,已描述了多种举例说明性的实施方案及其一些方面,修改和变更对本领域技术人员来说可以是显而易见的。 Thus, it has been described a variety of illustrative embodiments and with some aspects, modifications and variations to the skilled person may be apparent. 此类修改和变更旨在包括于本公开内容中,其仅是为举例说明的目的,并不旨在限制。 Such modifications and variations are intended to be included in the present disclosure, which is for illustrative purposes only and are not intended to be limiting. 本发明的范围应由对所附权利要求的适当解释及其等价形式来确定。 The scope of the invention should be determined appropriately interpreted appended claims and their equivalents.

Claims (20)

1. 制备制剂的方法,其包括: 在容器内提供混合物,所述混合物包含第一组合物和第二组合物; 使具有100千赫至100兆赫之频率和具有小于2厘米大小之聚焦区的聚焦声能传送穿过所述容器的壁,从而使所述混合物至少部分地置于所述聚焦区中; 通过代偿控制系统感知混合物的特征并调整聚焦声能系统的参数以实现通过将所述混合物暴露于所述聚焦声能而产生的乳剂或脂质体之纳米制剂的期望颗粒大小;和至少部分通过将所述混合物暴露于所述聚焦声能的所述聚焦区一段时间以在所述混合物中形成多个颗粒,以产生乳剂或脂质体的纳米制剂,在所述混合物暴露于所述聚焦区所述一段时间后,所述乳剂或脂质体的纳米制剂中的所述多个颗粒具有IOnm至400nm的平均大小。 A method of preparing a formulation, comprising: providing a mixture in a vessel, said mixture comprising a first composition and a second composition; so having a frequency of 100 kHz to 100 MHz the focal zone and having a size of less than 2 cm in focused acoustic energy is transmitted through the wall of the container, so that the mixture is at least partially disposed in the focal zone; perceived by the mixture and adjust the compensation control system wherein focused acoustic energy system parameters to achieve by the said mixture is exposed to a desired particle size of the nanoemulsion or the liposomes of the formulation focused acoustic energy is generated; at least partially by exposing the mixture to the focused acoustic energy to the focal zone for a period of time in the forming a plurality of particles of said mixture, to produce a nano-emulsion or liposome formulation, after exposure of the mixture to the focal zone for the period of time, the nano-emulsion or liposome formulation of the multi particles having an average size of IOnm to 400nm.
2. 根据权利要求1所述的方法,其中通过将所述混合物暴露于所述聚焦区一段时间所得的所述多个颗粒具有20nm至IOOnm的平均大小。 2. The method according to claim 1, wherein said mixture is exposed to by said plurality of particles of the resulting time period of the focusing region having an average size of 20nm to IOOnm.
3. 根据权利要求1所述的方法,其中所述混合物包含ImL至300mL的体积,且所述混合物中所述第一组合物的浓度是lmg/mL至lOOmg/mL所述混合物。 3. The method according to claim 1, wherein said mixture comprises ImL volume to 300mL, and the concentration of the mixture in the first composition is lmg / mL to lOOmg / mL of the mixture.
4. 根据权利要求1所述的方法,其中传送聚焦声能以将所述混合物暴露于所述聚焦区包括操作声能来源以产生所述混合物中所述多个颗粒的单峰分布。 4. The method according to claim 1, wherein the focused acoustic energy transmitted to the exposure of the mixture to the focal zone comprising operating said acoustic energy source to generate a plurality of particles of the mixture in a unimodal distribution.
5. 根据权利要求1所述的方法,其中传送聚焦声能以将所述混合物暴露于所述聚焦区包括操作声能来源以产生小于〇. 1的多分散指数。 5. The method according to claim 1, wherein the focused acoustic energy transmitted to the exposure of the mixture to the focal zone includes an operation to generate acoustic energy source is less than the square. Polydispersity index of 1.
6. 根据权利要求5所述的方法,其中传送聚焦声能以将所述混合物暴露于所述聚焦区包括操作声能来源以产生〇. 05至0. 1的多分散指数。 6. The method according to claim 5, wherein the focused acoustic energy transmitted to the exposure of the mixture to the focal zone comprises operating acoustic energy source to generate a square. Polydispersity index of 05 to 0.1.
7. 根据权利要求1所述的方法,其中所述第一组合物包含生物活性药物,其至少包括至少一种治疗剂或者选自DNA、siRNA、miRNA或质粒的多核苷酸材料。 7. The method according to claim 1, wherein said first composition comprises a biologically active agent comprising at least one therapeutic agent or at least a polynucleotide selected material DNA, siRNA, miRNA or plasmid.
8. 根据权利要求7所述的方法,其中所述第二组合物包含表面活性剂。 8. The method according to claim 7, wherein the second composition comprises a surfactant.
9. 根据权利要求1所述的方法,其中传送聚焦声能以将所述混合物暴露于所述聚焦区包括将所述混合物暴露于等温环境。 9. The method according to claim 1, wherein the focused acoustic energy transmitted to the exposure of the mixture to the focal zone comprises exposing the mixture to an isothermal environment.
10. 根据权利要求1所述的方法,其中所述多个颗粒包含含有活性成分的亲水液体材料或疏水液体材料,每个颗粒具有10纳米至400纳米的大小,并且还包含使所述颗粒悬浮的载体,所述载体包括与所述颗粒亲水性相反的液体。 10. The method according to claim 1, wherein said plurality of particles comprise a hydrophilic or hydrophobic liquid material is a liquid material containing the active ingredient, each having a particle size of 10 nanometers to 400 nanometers, and further comprising the particles suspension of a carrier comprising a hydrophilic particle with the opposite liquid.
11. 根据权利要求10所述的方法,其中所述乳剂或制剂没有大小大于400纳米或小于10纳米的颗粒。 11. The method according to claim 10, wherein the emulsion formulation or size is greater than 400 nm or not less than 10 nanometers.
12. 根据权利要求10所述的方法,其中所述乳剂或制剂表现出比通过其他方法产生之乳剂或制剂更长的保质期。 12. The method according to claim 10, wherein said emulsion formulation exhibits longer than or emulsion or formulation produced by other methods of shelf life.
13. 根据权利要求10所述的方法,其中所述乳剂或制剂表现出与通过其他方法产生之乳剂或制剂相比最低的污染水平,或其中所述乳剂或制剂是无菌的。 13. The method according to claim 10, wherein said emulsion formulation exhibits or compared to emulsions or other preparations produced by the method of the lowest pollution levels, or wherein the emulsion or formulation is sterile.
14. 根据权利要求10所述的方法,其中所述乳剂或制剂表现出较高的生物活性,导致较低的剂量以及较低的副作用和抗药性发生。 14. The method according to claim 10, wherein said emulsion formulation exhibits or higher biological activity, resulting in lower doses and less side effects and development of resistance.
15. 根据权利要求14所述的方法,其中所述较高的生物活性选自较高的药物代谢动力学活性和较低的肾清除率。 15. The method according to claim 14, wherein said high biological activity is selected from high kinetic activity of drug metabolism and lower renal clearance.
16. 根据权利要求10所述的方法,其中所述颗粒各自是疏水材料的微滴,其悬浮于亲水载体液体中。 16. The method of claim 10, wherein said particles each droplet of hydrophobic material, suspended in a hydrophilic carrier liquid.
17. 根据权利要求10所述的方法,其中所述颗粒各自是亲水材料的微滴,其悬浮于疏水载体液体中。 17. The method according to claim 10, wherein said particles each droplet is a hydrophilic material, suspended in the hydrophobic carrier liquid.
18. 根据权利要求1所述的方法,其中所述混合物包含活性成分、液体分散介质和液体载体,其中所述活性成分在所述介质中任选地具有大于3mg/ml的溶解度,并且其中所述活性成分和液体分散介质形成悬浮于所述液体载体中的所述颗粒。 18. The method according to claim 1, wherein the mixture comprising the active ingredient, the liquid dispersion medium and a liquid carrier, wherein the active ingredient has a solubility of greater than 3mg / ml in the medium is optionally, and wherein said active ingredient and a liquid dispersion medium forming the particles are suspended in the liquid carrier.
19. 根据权利要求18所述的方法,其中所述液体分散介质是疏水的,且所述液体载体是亲水的,或者其中所述液体分散介质是亲水的,且所述液体载体是疏水的。 19. The method according to claim 18, wherein said dispersing medium is a hydrophobic liquid, and the liquid carrier is hydrophilic, wherein the liquid or dispersion medium is hydrophilic, and the liquid carrier is hydrophobic of.
20. 根据权利要求1至19中任一项所述的方法,其中所述形成步骤产生乳剂。 20. The method according to claim 19, wherein said forming step to produce an emulsion.
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